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1.  A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol 
Genome-wide association analysis on monozygotic twin pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high density lipoprotein (HDL) cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (p = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1 261) which showed a moderate association for the variant (p = .002, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (p = 4.03 × 10−8).
doi:10.1017/thg.2012.63
PMCID: PMC4333218  PMID: 23031429
twins; association; lipids; apolipoproteins; interaction
2.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
3.  Metabolic Signatures of Adiposity in Young Adults: Mendelian Randomization Analysis and Effects of Weight Change 
PLoS Medicine  2014;11(12):e1001765.
In this study, Wurtz and colleagues investigated to what extent elevated body mass index (BMI) within the normal weight range has causal influences on the detailed systemic metabolite profile in early adulthood using Mendelian randomization analysis.
Please see later in the article for the Editors' Summary
Background
Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.
Methods and Findings
We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16–39 y; 51% women; mean ± standard deviation BMI 24±4 kg/m2). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%–183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87%±3%; R2 = 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160%±2%; R2 = 0.92).
Conclusions
Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Adiposity—having excessive body fat—is a growing global threat to public health. Body mass index (BMI, calculated by dividing a person's weight in kilograms by their height in meters squared) is a coarse indicator of excess body weight, but the measure is useful in large population studies. Compared to people with a lean body weight (a BMI of 18.5–24.9 kg/m2), individuals with higher BMI have an elevated risk of developing life-shortening cardiometabolic diseases—cardiovascular diseases that affect the heart and/or the blood vessels (for example, heart failure and stroke) and metabolic diseases that affect the cellular chemical reactions that sustain life (for example, diabetes). People become unhealthily fat by consuming food and drink that contains more energy (calories) than they need for their daily activities. So adiposity can be prevented and reversed by eating less and exercising more.
Why Was This Study Done?
Epidemiological studies, which record the patterns of risk factors and disease in populations, suggest that the illness and death associated with excess body weight is partly attributable to abnormalities in how individuals with high adiposity metabolize carbohydrates and fats, leading to higher blood sugar and cholesterol levels. Further, adiposity is also associated with many other deviations in the metabolic profile than these commonly measured risk factors. However, epidemiological studies cannot prove that adiposity causes specific changes in a person's systemic (overall) metabolic profile because individuals with high BMI may share other characteristics (confounding factors) that are the actual causes of both adiposity and metabolic abnormalities. Moreover, having a change in some aspect of metabolism could also lead to adiposity, rather than vice versa (reverse causation). Importantly, if there is a causal effect of adiposity on cardiometabolic risk factor levels, it might be possible to prevent the progression towards cardiometabolic diseases by weight loss. Here, the researchers use “Mendelian randomization” to examine whether increased BMI within the normal and overweight range is causally influencing the metabolic risk factors from many biological pathways during early adulthood. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. Several gene variants are known to lead to modestly increased BMI. Thus, an investigation of the associations between these gene variants and risk factors across the systemic metabolite profile in a population of healthy individuals can indicate whether higher BMI is causally related to known and novel metabolic risk factors and higher cardiometabolic disease risk.
What Did the Researchers Do and Find?
The researchers measured the BMI of 12,664 adolescents and young adults (average BMI 24.7 kg/m2) living in Finland and the blood levels of 82 metabolites in these young individuals at a single time point. Statistical analysis of these data indicated that elevated BMI was adversely associated with numerous cardiometabolic risk factors. For example, elevated BMI was associated with raised levels of low-density lipoprotein, “bad” cholesterol that increases cardiovascular disease risk. Next, the researchers used a gene score for predisposition to increased BMI, composed of 32 gene variants correlated with increased BMI, as an “instrumental variable” to assess whether adiposity causes metabolite abnormalities. The effects on the systemic metabolite profile of a 1-kg/m2 increment in BMI due to genetic predisposition closely matched the effects of an observed 1-kg/m2 increment in adulthood BMI on the metabolic profile. That is, higher levels of adiposity had causal effects on the levels of numerous blood-based metabolic risk factors, including higher levels of low-density lipoprotein cholesterol and triglyceride-carrying lipoproteins, protein markers of chronic inflammation and adverse liver function, impaired insulin sensitivity, and elevated concentrations of several amino acids that have recently been linked with the risk for developing diabetes. Elevated BMI also causally led to lower levels of certain high-density lipoprotein lipids in the blood, a marker for the risk of future cardiovascular disease. Finally, an examination of the metabolic changes associated with changes in BMI in 1,488 young adults after a period of six years showed that those metabolic measures that were most strongly associated with BMI at a single time point likewise displayed the highest responsiveness to weight change over time.
What Do These Findings Mean?
These findings suggest that increased adiposity has causal adverse effects on multiple cardiometabolic risk markers in non-obese young adults beyond the effects on cholesterol and blood sugar. Like all Mendelian randomization studies, the reliability of the causal association reported here depends on several assumptions made by the researchers. Nevertheless, these findings suggest that increased adiposity has causal adverse effects on multiple cardiometabolic risk markers in non-obese young adults. Importantly, the results of both the causal effect analyses and the longitudinal study suggest that there is no threshold below which a BMI increase does not adversely affect the metabolic profile, and that a systemic metabolic profile linked with high cardiometabolic disease risk that becomes established during early adulthood can be reversed. Overall, these findings therefore highlight the importance of weight reduction as a key target for metabolic risk factor control among young adults.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001765.
The Computational Medicine Research Team of the University of Oulu has a webpage that provides further information on metabolite profiling by high-throughput NMR metabolomics
The World Health Organization provides information on obesity (in several languages)
The Global Burden of Disease Study website provides the latest details about global obesity trends
The UK National Health Service Choices website provides information about obesity, cardiovascular disease, and type 2 diabetes (including some personal stories)
The American Heart Association provides information on all aspects of cardiovascular disease and diabetes and on keeping healthy; its website includes personal stories about heart attacks, stroke, and diabetes
The US Centers for Disease Control and Prevention has information on all aspects of overweight and obesity and information about heart disease, stroke, and diabetes
MedlinePlus provides links to other sources of information on heart disease, vascular disease, and obesity (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001765
PMCID: PMC4260795  PMID: 25490400
4.  Genome-wide association study identifies multiple loci influencing human serum metabolite levels 
Nature genetics  2012;44(3):269-276.
Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.
doi:10.1038/ng.1073
PMCID: PMC3605033  PMID: 22286219
5.  Influence of Serotonin Transporter Gene Polymorphism (5-HTTLPR Polymorphism) on the Relation between Brain 5-HT Transporter Binding and Heart Rate Corrected Cardiac Repolarization Interval 
PLoS ONE  2013;8(1):e50303.
Objective
Serotonin transporter gene polymorphism (5-HTTLPR polymorphism) predicts the degree of structural and functional connectivity in the brain, and less consistently the degree of vulnerability for anxiety and depressive disorders. It is less known how 5-HTTLPR polymorphism influences on the coupling between brain and neuronal cardiovascular control. The present study demonstrates the impact of 5-HTTLPR polymorphism on the relations between heart rate (HR) corrected cardiac repolarization interval (QTc interval) and the brain 5-HTT binding.
Material and Methods
Thirty healthy young adults (fifteen monozygotic twin pairs) (mean age 26±1.3 years, 16 females) were imagined with single-photon emission computed tomography (SPECT) using iodine-123 labeled 2β-carbomethoxy-3β-(4-iodophenyl) nortropane (nor-β-CIT). Continuous ECG recording was obtained from each participant at supine rest. Signal averaged QTc interval on continuous ECG was calculated and compared with the brain imaging results.
Results
In the two groups [l homozygotes (n = 16, 10 females), s carriers (n = 14, 8 female)] HR and the length of QTc interval were not influenced by 5-HTTLPR polymorphism. There were no significant relations between HR and 5-HTT binding in the brain. There were significant associations between QTc interval and nor-β-CIT binding in the brain in l homozygotes, but not in s carriers (correlations for QTc interval and nor-β-CIT binding of striatum, thalamus and right temporal region were −0.8–−0.9, (p<0.0005), respectively).
Conclusion
The finding of longer QTc interval with less 5-HTT binding availability in major serotonergic binding sites in l homozygotes, but not in s carriers, implicate to differentiated control of QTc interval by 5-HTTLPR polymorphism.
doi:10.1371/journal.pone.0050303
PMCID: PMC3544835  PMID: 23341873
6.  Adipose Co-expression networks across Finns and Mexicans identify novel triglyceride-associated genes 
BMC Medical Genomics  2012;5:61.
Background
High serum triglyceride (TG) levels is an established risk factor for coronary heart disease (CHD). Fat is stored in the form of TGs in human adipose tissue. We hypothesized that gene co-expression networks in human adipose tissue may be correlated with serum TG levels and help reveal novel genes involved in TG regulation.
Methods
Gene co-expression networks were constructed from two Finnish and one Mexican study sample using the blockwiseModules R function in Weighted Gene Co-expression Network Analysis (WGCNA). Overlap between TG-associated networks from each of the three study samples were calculated using a Fisher’s Exact test. Gene ontology was used to determine known pathways enriched in each TG-associated network.
Results
We measured gene expression in adipose samples from two Finnish and one Mexican study sample. In each study sample, we observed a gene co-expression network that was significantly associated with serum TG levels. The TG modules observed in Finns and Mexicans significantly overlapped and shared 34 genes. Seven of the 34 genes (ARHGAP30, CCR1, CXCL16, FERMT3, HCST, RNASET2, SELPG) were identified as the key hub genes of all three TG modules. Furthermore, two of the 34 genes (ARHGAP9, LST1) reside in previous TG GWAS regions, suggesting them as the regional candidates underlying the GWAS signals.
Conclusions
This study presents a novel adipose gene co-expression network with 34 genes significantly correlated with serum TG across populations.
doi:10.1186/1755-8794-5-61
PMCID: PMC3543280  PMID: 23217153
Mexicans; Finns; RNA sequencing; Triglycerides; Adipose tissue; Weighted gene co-expression network analysis
7.  Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma 
Chambers, John C | Zhang, Weihua | Sehmi, Joban | Li, Xinzhong | Wass, Mark N | Van der Harst, Pim | Holm, Hilma | Sanna, Serena | Kavousi, Maryam | Baumeister, Sebastian E | Coin, Lachlan J | Deng, Guohong | Gieger, Christian | Heard-Costa, Nancy L | Hottenga, Jouke-Jan | Kühnel, Brigitte | Kumar, Vinod | Lagou, Vasiliki | Liang, Liming | Luan, Jian’an | Vidal, Pedro Marques | Leach, Irene Mateo | O’Reilly, Paul F | Peden, John F | Rahmioglu, Nilufer | Soininen, Pasi | Speliotes, Elizabeth K | Yuan, Xin | Thorleifsson, Gudmar | Alizadeh, Behrooz Z | Atwood, Larry D | Borecki, Ingrid B | Brown, Morris J | Charoen, Pimphen | Cucca, Francesco | Das, Debashish | de Geus, Eco J C | Dixon, Anna L | Döring, Angela | Ehret, Georg | Eyjolfsson, Gudmundur I | Farrall, Martin | Forouhi, Nita G | Friedrich, Nele | Goessling, Wolfram | Gudbjartsson, Daniel F | Harris, Tamara B | Hartikainen, Anna-Liisa | Heath, Simon | Hirschfield, Gideon M | Hofman, Albert | Homuth, Georg | Hyppönen, Elina | Janssen, Harry L A | Johnson, Toby | Kangas, Antti J | Kema, Ido P | Kühn, Jens P | Lai, Sandra | Lathrop, Mark | Lerch, Markus M | Li, Yun | Liang, T Jake | Lin, Jing-Ping | Loos, Ruth J F | Martin, Nicholas G | Moffatt, Miriam F | Montgomery, Grant W | Munroe, Patricia B | Musunuru, Kiran | Nakamura, Yusuke | O’Donnell, Christopher J | Olafsson, Isleifur | Penninx, Brenda W | Pouta, Anneli | Prins, Bram P | Prokopenko, Inga | Puls, Ralf | Ruokonen, Aimo | Savolainen, Markku J | Schlessinger, David | Schouten, Jeoffrey N L | Seedorf, Udo | Sen-Chowdhry, Srijita | Siminovitch, Katherine A | Smit, Johannes H | Spector, Timothy D | Tan, Wenting | Teslovich, Tanya M | Tukiainen, Taru | Uitterlinden, Andre G | Van der Klauw, Melanie M | Vasan, Ramachandran S | Wallace, Chris | Wallaschofski, Henri | Wichmann, H-Erich | Willemsen, Gonneke | Würtz, Peter | Xu, Chun | Yerges-Armstrong, Laura M | Abecasis, Goncalo R | Ahmadi, Kourosh R | Boomsma, Dorret I | Caulfield, Mark | Cookson, William O | van Duijn, Cornelia M | Froguel, Philippe | Matsuda, Koichi | McCarthy, Mark I | Meisinger, Christa | Mooser, Vincent | Pietiläinen, Kirsi H | Schumann, Gunter | Snieder, Harold | Sternberg, Michael J E | Stolk, Ronald P | Thomas, Howard C | Thorsteinsdottir, Unnur | Uda, Manuela | Waeber, Gérard | Wareham, Nicholas J | Waterworth, Dawn M | Watkins, Hugh | Whitfield, John B | Witteman, Jacqueline C M | Wolffenbuttel, Bruce H R | Fox, Caroline S | Ala-Korpela, Mika | Stefansson, Kari | Vollenweider, Peter | Völzke, Henry | Schadt, Eric E | Scott, James | Järvelin, Marjo-Riitta | Elliott, Paul | Kooner, Jaspal S
Nature genetics  2011;43(11):1131-1138.
Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.
doi:10.1038/ng.970
PMCID: PMC3482372  PMID: 22001757
8.  Bacterial Endotoxin Activity in Human Serum Is Associated With Dyslipidemia, Insulin Resistance, Obesity, and Chronic Inflammation 
Diabetes Care  2011;34(8):1809-1815.
OBJECTIVE
To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN).
RESEARCH DESIGN AND METHODS
Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation.
RESULTS
The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1.
CONCLUSIONS
High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.
doi:10.2337/dc10-2197
PMCID: PMC3142060  PMID: 21636801
9.  Genetic architecture of circulating lipid levels 
Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
doi:10.1038/ejhg.2011.21
PMCID: PMC3137496  PMID: 21448234
serum lipids; polygenic; genome-wide association; polygenic score; pathway analysis
10.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function 
Artigas, María Soler | Loth, Daan W | Wain, Louise V | Gharib, Sina A | Obeidat, Ma’en | Tang, Wenbo | Zhai, Guangju | Zhao, Jing Hua | Smith, Albert Vernon | Huffman, Jennifer E | Albrecht, Eva | Jackson, Catherine M | Evans, David M | Cadby, Gemma | Fornage, Myriam | Manichaikul, Ani | Lopez, Lorna M | Johnson, Toby | Aldrich, Melinda C | Aspelund, Thor | Barroso, Inês | Campbell, Harry | Cassano, Patricia A | Couper, David J | Eiriksdottir, Gudny | Franceschini, Nora | Garcia, Melissa | Gieger, Christian | Gislason, Gauti Kjartan | Grkovic, Ivica | Hammond, Christopher J | Hancock, Dana B | Harris, Tamara B | Ramasamy, Adaikalavan | Heckbert, Susan R | Heliövaara, Markku | Homuth, Georg | Hysi, Pirro G | James, Alan L | Jankovic, Stipan | Joubert, Bonnie R | Karrasch, Stefan | Klopp, Norman | Koch, Beate | Kritchevsky, Stephen B | Launer, Lenore J | Liu, Yongmei | Loehr, Laura R | Lohman, Kurt | Loos, Ruth JF | Lumley, Thomas | Al Balushi, Khalid A | Ang, Wei Q | Barr, R Graham | Beilby, John | Blakey, John D | Boban, Mladen | Boraska, Vesna | Brisman, Jonas | Britton, John R | Brusselle, Guy G | Cooper, Cyrus | Curjuric, Ivan | Dahgam, Santosh | Deary, Ian J | Ebrahim, Shah | Eijgelsheim, Mark | Francks, Clyde | Gaysina, Darya | Granell, Raquel | Gu, Xiangjun | Hankinson, John L | Hardy, Rebecca | Harris, Sarah E | Henderson, John | Henry, Amanda | Hingorani, Aroon D | Hofman, Albert | Holt, Patrick G | Hui, Jennie | Hunter, Michael L | Imboden, Medea | Jameson, Karen A | Kerr, Shona M | Kolcic, Ivana | Kronenberg, Florian | Liu, Jason Z | Marchini, Jonathan | McKeever, Tricia | Morris, Andrew D | Olin, Anna-Carin | Porteous, David J | Postma, Dirkje S | Rich, Stephen S | Ring, Susan M | Rivadeneira, Fernando | Rochat, Thierry | Sayer, Avan Aihie | Sayers, Ian | Sly, Peter D | Smith, George Davey | Sood, Akshay | Starr, John M | Uitterlinden, André G | Vonk, Judith M | Wannamethee, S Goya | Whincup, Peter H | Wijmenga, Cisca | Williams, O Dale | Wong, Andrew | Mangino, Massimo | Marciante, Kristin D | McArdle, Wendy L | Meibohm, Bernd | Morrison, Alanna C | North, Kari E | Omenaas, Ernst | Palmer, Lyle J | Pietiläinen, Kirsi H | Pin, Isabelle | Polašek, Ozren | Pouta, Anneli | Psaty, Bruce M | Hartikainen, Anna-Liisa | Rantanen, Taina | Ripatti, Samuli | Rotter, Jerome I | Rudan, Igor | Rudnicka, Alicja R | Schulz, Holger | Shin, So-Youn | Spector, Tim D | Surakka, Ida | Vitart, Veronique | Völzke, Henry | Wareham, Nicholas J | Warrington, Nicole M | Wichmann, H-Erich | Wild, Sarah H | Wilk, Jemma B | Wjst, Matthias | Wright, Alan F | Zgaga, Lina | Zemunik, Tatijana | Pennell, Craig E | Nyberg, Fredrik | Kuh, Diana | Holloway, John W | Boezen, H Marike | Lawlor, Debbie A | Morris, Richard W | Probst-Hensch, Nicole | Kaprio, Jaakko | Wilson, James F | Hayward, Caroline | Kähönen, Mika | Heinrich, Joachim | Musk, Arthur W | Jarvis, Deborah L | Gläser, Sven | Järvelin, Marjo-Riitta | Stricker, Bruno H Ch | Elliott, Paul | O’Connor, George T | Strachan, David P | London, Stephanie J | Hall, Ian P | Gudnason, Vilmundur | Tobin, Martin D
Nature Genetics  2011;43(11):1082-1090.
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
doi:10.1038/ng.941
PMCID: PMC3267376  PMID: 21946350
11.  Genome-Wide Association Study to Identify Common Variants Associated with Brachial Circumference: A Meta-Analysis of 14 Cohorts 
PLoS ONE  2012;7(3):e31369.
Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.
doi:10.1371/journal.pone.0031369
PMCID: PMC3315559  PMID: 22479309
12.  An Investigation into the Relationship Between Soft Tissue Body Composition and Bone Mineral Density in a Young Adult Twin Sample 
The purpose of this study was to investigate the relationship of fat mass (FM) and lean mass (LM) with bone mineral density (BMD) independent of genetic effects. We also assessed the extent to which genetic and environmental influences explain the associations between these phenotypes. Body composition and BMD were measured using dual-energy X-ray absorptiometry in 57 monozygotic and 92 same-sex dizygotic twin pairs, aged 23 to 31 years, chosen to represent a wide range of intrapair differences in body mass index (BMI; 0 to 15.2 kg/m2). Heritability estimates were adjusted for height and gender. In multiple linear regression analysis, intrapair differences in both FM and LM were independently associated with intrapair differences in BMD at most skeletal sites after adjustment for gender and differences in height. Within monozygotic and dizygotic pairs, LM was a significantly stronger predictor of whole-body BMD than FM (p < .01). Additive genetic factors explained 87% [95% confidence interval (CI) 80%–91%), 81% (95% CI 70%–88%), and 61% (95% CI 41%–75%) of the variation in whole-body BMD, LM, and FM, respectively. Additive genetic factors also accounted for 69% to 88% of the covariance between LM and BMD and for 42% to 72% of the covariance between FM and BMD depending on the skeletal site. The genetic correlation between LM and whole-body BMD (rg = 0.46, 95% CI 0.32–0.58) was greater than that of FM and whole-body BMD (rg = 0.25, 95% CI 0.05–0.42). In conclusion, our data indicate that peak BMD is influenced by acquired body weight as well as genetic factors. In young adulthood, LM and BMD may have more genes in common than do FM and BMD. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.192
PMCID: PMC3179317  PMID: 20658559
BONE MINERAL DENSITY; FAT MASS; LEAN MASS; TWIN STUDIES; GENETIC CORRELATION
13.  Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans 
PLoS Biology  2011;9(6):e1000623.
The authors describe a new approach to studying cellular lipid profiles and propose a compensatory mechanism that may help maintain the normal membrane function of adipocytes in the context of obesity.
Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
Author Summary
Obesity is characterized by excess body fat, which is predominantly stored in the adipose tissue. When adipose tissue expands too much it stops storing lipid appropriately. The excess lipid accumulates in organs such as muscle, liver, and pancreas, causing metabolic disease. In this study, we aim to identify factors that cause adipose tissue to malfunction when it reaches its limit of expansion. We performed lipidomic analyses of human adipose tissue in twin pairs discordant for obesity—that is, one of the twins was lean and one was obese—but still metabolically healthy. We identified multiple changes in membrane phospholipids. Using computer modeling, we show that “lean” and “obese” membrane lipid compositions have the same physical properties despite their different compositions. We hypothesize that this represents allostasis—changes in lipid membrane composition in obesity occur to protect the physical properties of the membranes. However, protective changes cannot occur without a cost, and accordingly we demonstrate that switching to the “obese” lipid composition is associated with higher levels of adipose tissue inflammation. In a separate group of metabolically unhealthy obese individuals we investigated how the processes that regulate the “lean” and “obese” lipid profiles are changed. To determine how these lipid membrane changes are regulated we constructed an in silico network model that identified key control points and potential molecular players. We validated this network by performing genetic manipulations in cell models. Therapeutic targeting of this network may open new opportunities for the prevention or treatment of obesity-related metabolic complications.
doi:10.1371/journal.pbio.1000623
PMCID: PMC3110175  PMID: 21666801
14.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 
Heid, Iris M. | Jackson, Anne U. | Randall, Joshua C. | Winkler, Thomas W. | Qi, Lu | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Zillikens, M. Carola | Speliotes, Elizabeth K. | Mägi, Reedik | Workalemahu, Tsegaselassie | White, Charles C. | Bouatia-Naji, Nabila | Harris, Tamara B. | Berndt, Sonja I. | Ingelsson, Erik | Willer, Cristen J. | Weedon, Michael N. | Luan, Jian'an | Vedantam, Sailaja | Esko, Tõnu | Kilpeläinen, Tuomas O. | Kutalik, Zoltán | Li, Shengxu | Monda, Keri L. | Dixon, Anna L. | Holmes, Christopher C. | Kaplan, Lee M. | Liang, Liming | Min, Josine L. | Moffatt, Miriam F. | Molony, Cliona | Nicholson, George | Schadt, Eric E. | Zondervan, Krina T. | Feitosa, Mary F. | Ferreira, Teresa | Allen, Hana Lango | Weyant, Robert J. | Wheeler, Eleanor | Wood, Andrew R. | Estrada, Karol | Goddard, Michael E. | Lettre, Guillaume | Mangino, Massimo | Nyholt, Dale R. | Purcell, Shaun | Vernon Smith, Albert | Visscher, Peter M. | Yang, Jian | McCaroll, Steven A. | Nemesh, James | Voight, Benjamin F. | Absher, Devin | Amin, Najaf | Aspelund, Thor | Coin, Lachlan | Glazer, Nicole L. | Hayward, Caroline | Heard-Costa, Nancy L. | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kapur, Karen | Ketkar, Shamika | Knowles, Joshua W. | Kraft, Peter | Kraja, Aldi T. | Lamina, Claudia | Leitzmann, Michael F. | McKnight, Barbara | Morris, Andrew P. | Ong, Ken K. | Perry, John R.B. | Peters, Marjolein J. | Polasek, Ozren | Prokopenko, Inga | Rayner, Nigel W. | Ripatti, Samuli | Rivadeneira, Fernando | Robertson, Neil R. | Sanna, Serena | Sovio, Ulla | Surakka, Ida | Teumer, Alexander | van Wingerden, Sophie | Vitart, Veronique | Zhao, Jing Hua | Cavalcanti-Proença, Christine | Chines, Peter S. | Fisher, Eva | Kulzer, Jennifer R. | Lecoeur, Cecile | Narisu, Narisu | Sandholt, Camilla | Scott, Laura J. | Silander, Kaisa | Stark, Klaus | Tammesoo, Mari-Liis | Teslovich, Tanya M. | John Timpson, Nicholas | Watanabe, Richard M. | Welch, Ryan | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Kettunen, Johannes | Lawrence, Robert W. | Pellikka, Niina | Perola, Markus | Vandenput, Liesbeth | Alavere, Helene | Almgren, Peter | Atwood, Larry D. | Bennett, Amanda J. | Biffar, Reiner | Bonnycastle, Lori L. | Bornstein, Stefan R. | Buchanan, Thomas A. | Campbell, Harry | Day, Ian N.M. | Dei, Mariano | Dörr, Marcus | Elliott, Paul | Erdos, Michael R. | Eriksson, Johan G. | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Geus, Eco J.C. | Gjesing, Anette P. | Grallert, Harald | Gräßler, Jürgen | Groves, Christopher J. | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Havulinna, Aki S. | Herzig, Karl-Heinz | Hicks, Andrew A. | Hui, Jennie | Igl, Wilmar | Jousilahti, Pekka | Jula, Antti | Kajantie, Eero | Kinnunen, Leena | Kolcic, Ivana | Koskinen, Seppo | Kovacs, Peter | Kroemer, Heyo K. | Krzelj, Vjekoslav | Kuusisto, Johanna | Kvaloy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lathrop, G. Mark | Lokki, Marja-Liisa | Luben, Robert N. | Ludwig, Barbara | McArdle, Wendy L. | McCarthy, Anne | Morken, Mario A. | Nelis, Mari | Neville, Matt J. | Paré, Guillaume | Parker, Alex N. | Peden, John F. | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Pouta, Anneli | Ridderstråle, Martin | Samani, Nilesh J. | Saramies, Jouko | Sinisalo, Juha | Smit, Jan H. | Strawbridge, Rona J. | Stringham, Heather M. | Swift, Amy J. | Teder-Laving, Maris | Thomson, Brian | Usala, Gianluca | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Volpato, Claudia B. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Zgaga, Lina | Zitting, Paavo | Beilby, John P. | James, Alan L. | Kähönen, Mika | Lehtimäki, Terho | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Raitakari, Olli | Ridker, Paul M. | Stumvoll, Michael | Tönjes, Anke | Viikari, Jorma | Balkau, Beverley | Ben-Shlomo, Yoav | Bergman, Richard N. | Boeing, Heiner | Smith, George Davey | Ebrahim, Shah | Froguel, Philippe | Hansen, Torben | Hengstenberg, Christian | Hveem, Kristian | Isomaa, Bo | Jørgensen, Torben | Karpe, Fredrik | Khaw, Kay-Tee | Laakso, Markku | Lawlor, Debbie A. | Marre, Michel | Meitinger, Thomas | Metspalu, Andres | Midthjell, Kristian | Pedersen, Oluf | Salomaa, Veikko | Schwarz, Peter E.H. | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Valle, Timo T. | Wareham, Nicholas J. | Arnold, Alice M. | Beckmann, Jacques S. | Bergmann, Sven | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Collins, Francis S. | Eiriksdottir, Gudny | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Hattersley, Andrew T. | Hofman, Albert | Hu, Frank B. | Illig, Thomas | Iribarren, Carlos | Jarvelin, Marjo-Riitta | Kao, W.H. Linda | Kaprio, Jaakko | Launer, Lenore J. | Munroe, Patricia B. | Oostra, Ben | Penninx, Brenda W. | Pramstaller, Peter P. | Psaty, Bruce M. | Quertermous, Thomas | Rissanen, Aila | Rudan, Igor | Shuldiner, Alan R. | Soranzo, Nicole | Spector, Timothy D. | Syvanen, Ann-Christine | Uda, Manuela | Uitterlinden, André | Völzke, Henry | Vollenweider, Peter | Wilson, James F. | Witteman, Jacqueline C. | Wright, Alan F. | Abecasis, Gonçalo R. | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Frayling, Timothy M. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | North, Kari E. | O'Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | Hirschhorn, Joel N. | Assimes, Themistocles L. | Wichmann, H.-Erich | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Stefansson, Kari | Cupples, L. Adrienne | Loos, Ruth J.F. | Barroso, Inês | McCarthy, Mark I. | Fox, Caroline S. | Mohlke, Karen L. | Lindgren, Cecilia M.
Nature genetics  2010;42(11):949-960.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body-mass-index (up to 77,167 participants), following up 16 loci in an additional 29 studies (up to 113,636 subjects). We identified 13 novel loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1, and CPEB4 (P 1.9 × 10−9 to 1.8 × 10−40), and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex-difference 1.9 × 10−3 to 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution, independent of overall adiposity, and reveal powerful gene-by-sex interactions.
doi:10.1038/ng.685
PMCID: PMC3000924  PMID: 20935629
genome-wide association; waist-hip-ratio; body fat distribution; central obesity; meta-analysis; genetics; visceral adipose tissue; metabolism; body composition; Expression Quantitative Trait Loci; sex difference
15.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 
Heid, Iris M | Jackson, Anne U | Randall, Joshua C | Winkler, Thomas W | Qi, Lu | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Zillikens, M Carola | Speliotes, Elizabeth K | Mägi, Reedik | Workalemahu, Tsegaselassie | White, Charles C | Bouatia-Naji, Nabila | Harris, Tamara B | Berndt, Sonja I | Ingelsson, Erik | Willer, Cristen J | Weedon, Michael N | Luan, Jian’An | Vedantam, Sailaja | Esko, Tõnu | Kilpeläinen, Tuomas O | Kutalik, Zoltán | Li, Shengxu | Monda, Keri L | Dixon, Anna L | Holmes, Christopher C | Kaplan, Lee M | Liang, Liming | Min, Josine L | Moffatt, Miriam F | Molony, Cliona | Nicholson, George | Schadt, Eric E | Zondervan, Krina T | Feitosa, Mary F | Ferreira, Teresa | Allen, Hana Lango | Weyant, Robert J | Wheeler, Eleanor | Wood, Andrew R | Estrada, Karol | Goddard, Michael E | Lettre, Guillaume | Mangino, Massimo | Nyholt, Dale R | Purcell, Shaun | Smith, Albert Vernon | Visscher, Peter M | Yang, Jian | McCarroll, Steven A | Nemesh, James | Voight, Benjamin F | Absher, Devin | Amin, Najaf | Aspelund, Thor | Coin, Lachlan | Glazer, Nicole L | Hayward, Caroline | Heard-costa, Nancy L | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kapur, Karen | Ketkar, Shamika | Knowles, Joshua W | Kraft, Peter | Kraja, Aldi T | Lamina, Claudia | Leitzmann, Michael F | McKnight, Barbara | Morris, Andrew P | Ong, Ken K | Perry, John R B | Peters, Marjolein J | Polasek, Ozren | Prokopenko, Inga | Rayner, Nigel W | Ripatti, Samuli | Rivadeneira, Fernando | Robertson, Neil R | Sanna, Serena | Sovio, Ulla | Surakka, Ida | Teumer, Alexander | van Wingerden, Sophie | Vitart, Veronique | Zhao, Jing Hua | Cavalcanti-Proença, Christine | Chines, Peter S | Fisher, Eva | Kulzer, Jennifer R | Lecoeur, Cecile | Narisu, Narisu | Sandholt, Camilla | Scott, Laura J | Silander, Kaisa | Stark, Klaus | Tammesoo, Mari-Liis | Teslovich, Tanya M | Timpson, Nicholas John | Watanabe, Richard M | Welch, Ryan | Chasman, Daniel I | Cooper, Matthew N | Jansson, John-Olov | Kettunen, Johannes | Lawrence, Robert W | Pellikka, Niina | Perola, Markus | Vandenput, Liesbeth | Alavere, Helene | Almgren, Peter | Atwood, Larry D | Bennett, Amanda J | Biffar, Reiner | Bonnycastle, Lori L | Bornstein, Stefan R | Buchanan, Thomas A | Campbell, Harry | Day, Ian N M | Dei, Mariano | Dörr, Marcus | Elliott, Paul | Erdos, Michael R | Eriksson, Johan G | Freimer, Nelson B | Fu, Mao | Gaget, Stefan | Geus, Eco J C | Gjesing, Anette P | Grallert, Harald | Gräßler, Jürgen | Groves, Christopher J | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Havulinna, Aki S | Herzig, Karl-Heinz | Hicks, Andrew A | Hui, Jennie | Igl, Wilmar | Jousilahti, Pekka | Jula, Antti | Kajantie, Eero | Kinnunen, Leena | Kolcic, Ivana | Koskinen, Seppo | Kovacs, Peter | Kroemer, Heyo K | Krzelj, Vjekoslav | Kuusisto, Johanna | Kvaloy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lathrop, G Mark | Lokki, Marja-Liisa | Luben, Robert N | Ludwig, Barbara | McArdle, Wendy L | McCarthy, Anne | Morken, Mario A | Nelis, Mari | Neville, Matt J | Paré, Guillaume | Parker, Alex N | Peden, John F | Pichler, Irene | Pietiläinen, Kirsi H | Platou, Carl G P | Pouta, Anneli | Ridderstråle, Martin | Samani, Nilesh J | Saramies, Jouko | Sinisalo, Juha | Smit, Jan H | Strawbridge, Rona J | Stringham, Heather M | Swift, Amy J | Teder-Laving, Maris | Thomson, Brian | Usala, Gianluca | van Meurs, Joyce B J | van Ommen, Gert-Jan | Vatin, Vincent | Volpato, Claudia B | Wallaschofski, Henri | Walters, G Bragi | Widen, Elisabeth | Wild, Sarah H | Willemsen, Gonneke | Witte, Daniel R | Zgaga, Lina | Zitting, Paavo | Beilby, John P | James, Alan L | Kähönen, Mika | Lehtimäki, Terho | Nieminen, Markku S | Ohlsson, Claes | Palmer, Lyle J | Raitakari, Olli | Ridker, Paul M | Stumvoll, Michael | Tönjes, Anke | Viikari, Jorma | Balkau, Beverley | Ben-Shlomo, Yoav | Bergman, Richard N | Boeing, Heiner | Smith, George Davey | Ebrahim, Shah | Froguel, Philippe | Hansen, Torben | Hengstenberg, Christian | Hveem, Kristian | Isomaa, Bo | Jørgensen, Torben | Karpe, Fredrik | Khaw, Kay-Tee | Laakso, Markku | Lawlor, Debbie A | Marre, Michel | Meitinger, Thomas | Metspalu, Andres | Midthjell, Kristian | Pedersen, Oluf | Salomaa, Veikko | Schwarz, Peter E H | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Valle, Timo T | Wareham, Nicholas J | Arnold, Alice M | Beckmann, Jacques S | Bergmann, Sven | Boerwinkle, Eric | Boomsma, Dorret I | Caulfield, Mark J | Collins, Francis S | Eiriksdottir, Gudny | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Hattersley, Andrew T | Hofman, Albert | Hu, Frank B | Illig, Thomas | Iribarren, Carlos | Jarvelin, Marjo-Riitta | Kao, W H Linda | Kaprio, Jaakko | Launer, Lenore J | Munroe, Patricia B | Oostra, Ben | Penninx, Brenda W | Pramstaller, Peter P | Psaty, Bruce M | Quertermous, Thomas | Rissanen, Aila | Rudan, Igor | Shuldiner, Alan R | Soranzo, Nicole | Spector, Timothy D | Syvanen, Ann-Christine | Uda, Manuela | Uitterlinden, André | Völzke, Henry | Vollenweider, Peter | Wilson, James F | Witteman, Jacqueline C | Wright, Alan F | Abecasis, Gonçalo R | Boehnke, Michael | Borecki, Ingrid B | Deloukas, Panos | Frayling, Timothy M | Groop, Leif C | Haritunians, Talin | Hunter, David J | Kaplan, Robert C | North, Kari E | O’connell, Jeffrey R | Peltonen, Leena | Schlessinger, David | Strachan, David P | Hirschhorn, Joel N | Assimes, Themistocles L | Wichmann, H-Erich | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Stefansson, Kari | Cupples, L Adrienne | Loos, Ruth J F | Barroso, Inês | McCarthy, Mark I | Fox, Caroline S | Mohlke, Karen L | Lindgren, Cecilia M
Nature genetics  2010;42(11):949-960.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
doi:10.1038/ng.685
PMCID: PMC3000924  PMID: 20935629
16.  Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index 
Speliotes, Elizabeth K. | Willer, Cristen J. | Berndt, Sonja I. | Monda, Keri L. | Thorleifsson, Gudmar | Jackson, Anne U. | Allen, Hana Lango | Lindgren, Cecilia M. | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Vedantam, Sailaja | Winkler, Thomas W. | Qi, Lu | Workalemahu, Tsegaselassie | Heid, Iris M. | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Weedon, Michael N. | Wheeler, Eleanor | Wood, Andrew R. | Ferreira, Teresa | Weyant, Robert J. | Segré, Ayellet V. | Estrada, Karol | Liang, Liming | Nemesh, James | Park, Ju-Hyun | Gustafsson, Stefan | Kilpeläinen, Tuomas O. | Yang, Jian | Bouatia-Naji, Nabila | Esko, Tõnu | Feitosa, Mary F. | Kutalik, Zoltán | Mangino, Massimo | Raychaudhuri, Soumya | Scherag, Andre | Smith, Albert Vernon | Welch, Ryan | Zhao, Jing Hua | Aben, Katja K. | Absher, Devin M. | Amin, Najaf | Dixon, Anna L. | Fisher, Eva | Glazer, Nicole L. | Goddard, Michael E. | Heard-Costa, Nancy L. | Hoesel, Volker | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Ketkar, Shamika | Lamina, Claudia | Li, Shengxu | Moffatt, Miriam F. | Myers, Richard H. | Narisu, Narisu | Perry, John R.B. | Peters, Marjolein J. | Preuss, Michael | Ripatti, Samuli | Rivadeneira, Fernando | Sandholt, Camilla | Scott, Laura J. | Timpson, Nicholas J. | Tyrer, Jonathan P. | van Wingerden, Sophie | Watanabe, Richard M. | White, Charles C. | Wiklund, Fredrik | Barlassina, Christina | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Lawrence, Robert W. | Pellikka, Niina | Prokopenko, Inga | Shi, Jianxin | Thiering, Elisabeth | Alavere, Helene | Alibrandi, Maria T. S. | Almgren, Peter | Arnold, Alice M. | Aspelund, Thor | Atwood, Larry D. | Balkau, Beverley | Balmforth, Anthony J. | Bennett, Amanda J. | Ben-Shlomo, Yoav | Bergman, Richard N. | Bergmann, Sven | Biebermann, Heike | Blakemore, Alexandra I.F. | Boes, Tanja | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brown, Morris J. | Buchanan, Thomas A. | Busonero, Fabio | Campbell, Harry | Cappuccio, Francesco P. | Cavalcanti-Proença, Christine | Chen, Yii-Der Ida | Chen, Chih-Mei | Chines, Peter S. | Clarke, Robert | Coin, Lachlan | Connell, John | Day, Ian N.M. | Heijer, Martin den | Duan, Jubao | Ebrahim, Shah | Elliott, Paul | Elosua, Roberto | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Facheris, Maurizio F. | Felix, Stephan B. | Fischer-Posovszky, Pamela | Folsom, Aaron R. | Friedrich, Nele | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Gejman, Pablo V. | Geus, Eco J.C. | Gieger, Christian | Gjesing, Anette P. | Goel, Anuj | Goyette, Philippe | Grallert, Harald | Gräßler, Jürgen | Greenawalt, Danielle M. | Groves, Christopher J. | Gudnason, Vilmundur | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hall, Alistair S. | Havulinna, Aki S. | Hayward, Caroline | Heath, Andrew C. | Hengstenberg, Christian | Hicks, Andrew A. | Hinney, Anke | Hofman, Albert | Homuth, Georg | Hui, Jennie | Igl, Wilmar | Iribarren, Carlos | Isomaa, Bo | Jacobs, Kevin B. | Jarick, Ivonne | Jewell, Elizabeth | John, Ulrich | Jørgensen, Torben | Jousilahti, Pekka | Jula, Antti | Kaakinen, Marika | Kajantie, Eero | Kaplan, Lee M. | Kathiresan, Sekar | Kettunen, Johannes | Kinnunen, Leena | Knowles, Joshua W. | Kolcic, Ivana | König, Inke R. | Koskinen, Seppo | Kovacs, Peter | Kuusisto, Johanna | Kraft, Peter | Kvaløy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lanzani, Chiara | Launer, Lenore J. | Lecoeur, Cecile | Lehtimäki, Terho | Lettre, Guillaume | Liu, Jianjun | Lokki, Marja-Liisa | Lorentzon, Mattias | Luben, Robert N. | Ludwig, Barbara | Manunta, Paolo | Marek, Diana | Marre, Michel | Martin, Nicholas G. | McArdle, Wendy L. | McCarthy, Anne | McKnight, Barbara | Meitinger, Thomas | Melander, Olle | Meyre, David | Midthjell, Kristian | Montgomery, Grant W. | Morken, Mario A. | Morris, Andrew P. | Mulic, Rosanda | Ngwa, Julius S. | Nelis, Mari | Neville, Matt J. | Nyholt, Dale R. | O’Donnell, Christopher J. | O’Rahilly, Stephen | Ong, Ken K. | Oostra, Ben | Paré, Guillaume | Parker, Alex N. | Perola, Markus | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Polasek, Ozren | Pouta, Anneli | Rafelt, Suzanne | Raitakari, Olli | Rayner, Nigel W. | Ridderstråle, Martin | Rief, Winfried | Ruokonen, Aimo | Robertson, Neil R. | Rzehak, Peter | Salomaa, Veikko | Sanders, Alan R. | Sandhu, Manjinder S. | Sanna, Serena | Saramies, Jouko | Savolainen, Markku J. | Scherag, Susann | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Silander, Kaisa | Sinisalo, Juha | Siscovick, David S. | Smit, Jan H. | Soranzo, Nicole | Sovio, Ulla | Stephens, Jonathan | Surakka, Ida | Swift, Amy J. | Tammesoo, Mari-Liis | Tardif, Jean-Claude | Teder-Laving, Maris | Teslovich, Tanya M. | Thompson, John R. | Thomson, Brian | Tönjes, Anke | Tuomi, Tiinamaija | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Viikari, Jorma | Visvikis-Siest, Sophie | Vitart, Veronique | Vogel, Carla I. G. | Voight, Benjamin F. | Waite, Lindsay L. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wiegand, Susanna | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Witteman, Jacqueline C. | Xu, Jianfeng | Zhang, Qunyuan | Zgaga, Lina | Ziegler, Andreas | Zitting, Paavo | Beilby, John P. | Farooqi, I. Sadaf | Hebebrand, Johannes | Huikuri, Heikki V. | James, Alan L. | Kähönen, Mika | Levinson, Douglas F. | Macciardi, Fabio | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Ridker, Paul M. | Stumvoll, Michael | Beckmann, Jacques S. | Boeing, Heiner | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Collins, Francis S. | Cupples, L. Adrienne | Smith, George Davey | Erdmann, Jeanette | Froguel, Philippe | Grönberg, Henrik | Gyllensten, Ulf | Hall, Per | Hansen, Torben | Harris, Tamara B. | Hattersley, Andrew T. | Hayes, Richard B. | Heinrich, Joachim | Hu, Frank B. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Kaprio, Jaakko | Karpe, Fredrik | Khaw, Kay-Tee | Kiemeney, Lambertus A. | Krude, Heiko | Laakso, Markku | Lawlor, Debbie A. | Metspalu, Andres | Munroe, Patricia B. | Ouwehand, Willem H. | Pedersen, Oluf | Penninx, Brenda W. | Peters, Annette | Pramstaller, Peter P. | Quertermous, Thomas | Reinehr, Thomas | Rissanen, Aila | Rudan, Igor | Samani, Nilesh J. | Schwarz, Peter E.H. | Shuldiner, Alan R. | Spector, Timothy D. | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André | Valle, Timo T. | Wabitsch, Martin | Waeber, Gérard | Wareham, Nicholas J. | Watkins, Hugh | Wilson, James F. | Wright, Alan F. | Zillikens, M. Carola | Chatterjee, Nilanjan | McCarroll, Steven A. | Purcell, Shaun | Schadt, Eric E. | Visscher, Peter M. | Assimes, Themistocles L. | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | Mohlke, Karen L. | O’Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | van Duijn, Cornelia M. | Wichmann, H.-Erich | Frayling, Timothy M. | Thorsteinsdottir, Unnur | Abecasis, Gonçalo R. | Barroso, Inês | Boehnke, Michael | Stefansson, Kari | North, Kari E. | McCarthy, Mark I. | Hirschhorn, Joel N. | Ingelsson, Erik | Loos, Ruth J.F.
Nature genetics  2010;42(11):937-948.
Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.
doi:10.1038/ng.686
PMCID: PMC3014648  PMID: 20935630
17.  Hundreds of variants clustered in genomic loci and biological pathways affect human height 
Lango Allen, Hana | Estrada, Karol | Lettre, Guillaume | Berndt, Sonja I. | Weedon, Michael N. | Rivadeneira, Fernando | Willer, Cristen J. | Jackson, Anne U. | Vedantam, Sailaja | Raychaudhuri, Soumya | Ferreira, Teresa | Wood, Andrew R. | Weyant, Robert J. | Segrè, Ayellet V. | Speliotes, Elizabeth K. | Wheeler, Eleanor | Soranzo, Nicole | Park, Ju-Hyun | Yang, Jian | Gudbjartsson, Daniel | Heard-Costa, Nancy L. | Randall, Joshua C. | Qi, Lu | Smith, Albert Vernon | Mägi, Reedik | Pastinen, Tomi | Liang, Liming | Heid, Iris M. | Luan, Jian'an | Thorleifsson, Gudmar | Winkler, Thomas W. | Goddard, Michael E. | Lo, Ken Sin | Palmer, Cameron | Workalemahu, Tsegaselassie | Aulchenko, Yurii S. | Johansson, Åsa | Zillikens, M.Carola | Feitosa, Mary F. | Esko, Tõnu | Johnson, Toby | Ketkar, Shamika | Kraft, Peter | Mangino, Massimo | Prokopenko, Inga | Absher, Devin | Albrecht, Eva | Ernst, Florian | Glazer, Nicole L. | Hayward, Caroline | Hottenga, Jouke-Jan | Jacobs, Kevin B. | Knowles, Joshua W. | Kutalik, Zoltán | Monda, Keri L. | Polasek, Ozren | Preuss, Michael | Rayner, Nigel W. | Robertson, Neil R. | Steinthorsdottir, Valgerdur | Tyrer, Jonathan P. | Voight, Benjamin F. | Wiklund, Fredrik | Xu, Jianfeng | Zhao, Jing Hua | Nyholt, Dale R. | Pellikka, Niina | Perola, Markus | Perry, John R.B. | Surakka, Ida | Tammesoo, Mari-Liis | Altmaier, Elizabeth L. | Amin, Najaf | Aspelund, Thor | Bhangale, Tushar | Boucher, Gabrielle | Chasman, Daniel I. | Chen, Constance | Coin, Lachlan | Cooper, Matthew N. | Dixon, Anna L. | Gibson, Quince | Grundberg, Elin | Hao, Ke | Junttila, M. Juhani | Kaplan, Lee M. | Kettunen, Johannes | König, Inke R. | Kwan, Tony | Lawrence, Robert W. | Levinson, Douglas F. | Lorentzon, Mattias | McKnight, Barbara | Morris, Andrew P. | Müller, Martina | Ngwa, Julius Suh | Purcell, Shaun | Rafelt, Suzanne | Salem, Rany M. | Salvi, Erika | Sanna, Serena | Shi, Jianxin | Sovio, Ulla | Thompson, John R. | Turchin, Michael C. | Vandenput, Liesbeth | Verlaan, Dominique J. | Vitart, Veronique | White, Charles C. | Ziegler, Andreas | Almgren, Peter | Balmforth, Anthony J. | Campbell, Harry | Citterio, Lorena | De Grandi, Alessandro | Dominiczak, Anna | Duan, Jubao | Elliott, Paul | Elosua, Roberto | Eriksson, Johan G. | Freimer, Nelson B. | Geus, Eco J.C. | Glorioso, Nicola | Haiqing, Shen | Hartikainen, Anna-Liisa | Havulinna, Aki S. | Hicks, Andrew A. | Hui, Jennie | Igl, Wilmar | Illig, Thomas | Jula, Antti | Kajantie, Eero | Kilpeläinen, Tuomas O. | Koiranen, Markku | Kolcic, Ivana | Koskinen, Seppo | Kovacs, Peter | Laitinen, Jaana | Liu, Jianjun | Lokki, Marja-Liisa | Marusic, Ana | Maschio, Andrea | Meitinger, Thomas | Mulas, Antonella | Paré, Guillaume | Parker, Alex N. | Peden, John F. | Petersmann, Astrid | Pichler, Irene | Pietiläinen, Kirsi H. | Pouta, Anneli | Ridderstråle, Martin | Rotter, Jerome I. | Sambrook, Jennifer G. | Sanders, Alan R. | Schmidt, Carsten Oliver | Sinisalo, Juha | Smit, Jan H. | Stringham, Heather M. | Walters, G.Bragi | Widen, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Zagato, Laura | Zgaga, Lina | Zitting, Paavo | Alavere, Helene | Farrall, Martin | McArdle, Wendy L. | Nelis, Mari | Peters, Marjolein J. | Ripatti, Samuli | van Meurs, Joyce B.J. | Aben, Katja K. | Ardlie, Kristin G | Beckmann, Jacques S. | Beilby, John P. | Bergman, Richard N. | Bergmann, Sven | Collins, Francis S. | Cusi, Daniele | den Heijer, Martin | Eiriksdottir, Gudny | Gejman, Pablo V. | Hall, Alistair S. | Hamsten, Anders | Huikuri, Heikki V. | Iribarren, Carlos | Kähönen, Mika | Kaprio, Jaakko | Kathiresan, Sekar | Kiemeney, Lambertus | Kocher, Thomas | Launer, Lenore J. | Lehtimäki, Terho | Melander, Olle | Mosley, Tom H. | Musk, Arthur W. | Nieminen, Markku S. | O'Donnell, Christopher J. | Ohlsson, Claes | Oostra, Ben | Palmer, Lyle J. | Raitakari, Olli | Ridker, Paul M. | Rioux, John D. | Rissanen, Aila | Rivolta, Carlo | Schunkert, Heribert | Shuldiner, Alan R. | Siscovick, David S. | Stumvoll, Michael | Tönjes, Anke | Tuomilehto, Jaakko | van Ommen, Gert-Jan | Viikari, Jorma | Heath, Andrew C. | Martin, Nicholas G. | Montgomery, Grant W. | Province, Michael A. | Kayser, Manfred | Arnold, Alice M. | Atwood, Larry D. | Boerwinkle, Eric | Chanock, Stephen J. | Deloukas, Panos | Gieger, Christian | Grönberg, Henrik | Hall, Per | Hattersley, Andrew T. | Hengstenberg, Christian | Hoffman, Wolfgang | Lathrop, G.Mark | Salomaa, Veikko | Schreiber, Stefan | Uda, Manuela | Waterworth, Dawn | Wright, Alan F. | Assimes, Themistocles L. | Barroso, Inês | Hofman, Albert | Mohlke, Karen L. | Boomsma, Dorret I. | Caulfield, Mark J. | Cupples, L.Adrienne | Erdmann, Jeanette | Fox, Caroline S. | Gudnason, Vilmundur | Gyllensten, Ulf | Harris, Tamara B. | Hayes, Richard B. | Jarvelin, Marjo-Riitta | Mooser, Vincent | Munroe, Patricia B. | Ouwehand, Willem H. | Penninx, Brenda W. | Pramstaller, Peter P. | Quertermous, Thomas | Rudan, Igor | Samani, Nilesh J. | Spector, Timothy D. | Völzke, Henry | Watkins, Hugh | Wilson, James F. | Groop, Leif C. | Haritunians, Talin | Hu, Frank B. | Kaplan, Robert C. | Metspalu, Andres | North, Kari E. | Schlessinger, David | Wareham, Nicholas J. | Hunter, David J. | O'Connell, Jeffrey R. | Strachan, David P. | Wichmann, H.-Erich | Borecki, Ingrid B. | van Duijn, Cornelia M. | Schadt, Eric E. | Thorsteinsdottir, Unnur | Peltonen, Leena | Uitterlinden, André | Visscher, Peter M. | Chatterjee, Nilanjan | Loos, Ruth J.F. | Boehnke, Michael | McCarthy, Mark I. | Ingelsson, Erik | Lindgren, Cecilia M. | Abecasis, Gonçalo R. | Stefansson, Kari | Frayling, Timothy M. | Hirschhorn, Joel N
Nature  2010;467(7317):832-838.
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence phenotype. Genome-wide association (GWA) studies have identified >600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the utility of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P=0.016), and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants, and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented amongst variants that alter amino acid structure of proteins and expression levels of nearby genes. Our data explain ∼10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to ∼16% of phenotypic variation (∼20% of heritable variation). Although additional approaches are needed to fully dissect the genetic architecture of polygenic human traits, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
doi:10.1038/nature09410
PMCID: PMC2955183  PMID: 20881960
18.  The Effect of Alcohol Consumption on Later Obesity in Early Adulthood — A Population-based Longitudinal Study 
Aims: The study aimed to determine whether alcohol use during late adolescence contributes to the weight gain from adolescence to young adulthood or risk of obesity or waist circumference at young adulthood.
Methods: A population-based, longitudinal study of 5563 Finnish twins born in 1975–1979 and surveyed at ages 16 (T1), 17 (T2), 18 (T3) and 23–27 (T4) years. Drinking habits, height and weight were self-reported at T1, T2, T3 and T4; waist circumference was self-measured at T4. As potential confounders, we used smoking, diet, physical activity, place of residence, socio-economic status and parents' body mass index (BMI).
Results: Compared to the reference group (drinking once to twice per month), the BMI increase from T3 to T4 was less among abstaining men (−0.62 kg/m2, (95% CI −1.04, −0.20)) and among women in those drinking less than monthly (−0.38 kg/m2, (−0.71, −0.04)). In women, at least weekly drinking was associated with larger waist circumference (Beta 1.55 cm, (0.48, 2.61)), but this became statistically non-significant after adjusting for potential confounders. In a multilevel model for change, drinking frequency was not associated with weight change in women; in men, a negative association was seen, but it was statistically non-significant after adjusting for potential confounders.
Conclusions: These results from a population-based study with a large set of confounding variables suggest that alcohol use during adolescence has at most a minor effect on weight gain or development of abdominal obesity from adolescence to young adulthood.
doi:10.1093/alcalc/agp090
PMCID: PMC2842105  PMID: 20071348
19.  Use of Genome-Wide Expression Data to Mine the “Gray Zone” of GWA Studies Leads to Novel Candidate Obesity Genes 
PLoS Genetics  2010;6(6):e1000976.
To get beyond the “low-hanging fruits” so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24–28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N = 77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N = 21,000) revealed a significant deviation of P-values from the expected (P = 4×10−4). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of ∼2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity.
Author Summary
Obesity has a strong genetic component and an estimated 45%–85% of the variation in adult relative weight is genetically determined. Many genes have recently been identified in genome-wide association studies. The individual effects of the identified genes, however, have been very modest, and their identification required very large sample sizes. New approaches are therefore needed to uncover further genetic variants that contribute to the development of obesity and related conditions. Much can be learned from studying the expression of genes in adipose tissue of obese and non-obese subjects, but it is very difficult to distinguish which genes' expression differences represent reactions to obesity from those related to causal processes. We studied monozygotic twin pairs discordant for obesity and contrasted the gene expression profiles of obese and lean co-twins (controlling for genetic variation) to those from unrelated individuals to try to discern the cause-and-effect relationships of the identified changes in gene expression in fat. Testing the identified genes in 21,000 individuals identified numerous new genes with possible roles in the development of obesity. Among the top findings was a gene involved in blood coagulation (Factor XIIIA1), possibly linking obesity with known complications including deep vein thrombosis, heart attack, and stroke.
doi:10.1371/journal.pgen.1000976
PMCID: PMC2880558  PMID: 20532202
20.  Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity  
PLoS Medicine  2008;5(3):e51.
Background
The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.
Methods and Findings
We used a special study design of “clonal controls,” rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean ± standard deviation (SD) age 25.8 ± 1.4 y and a body mass index (BMI) difference 5.2 ± 1.8 kg/m2. Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.
Conclusions
Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
Leena Peltonen and colleagues uncover the metabolic changes that result from obesity through an analysis of genetically identical twin pairs in which one was obese and the other was not.
Editors' Summary
Background.
Around the world, the proportion of people who are obese (people with an unhealthy amount of body fat) is increasing. In the US, for example, 1 adult in 7 was obese in the mid 1970s. That is, their body mass index (BMI)—their weight in kilograms divided by their height in meters squared—was more than 30. Nowadays, 1 US adult in 3 has a BMI this high and, by 2025, it is predicted that 1 in 2 will be obese. This obesity epidemic is being driven by lifestyle changes that encourage the over-consumption of energy-rich foods and discourage regular physical activity. The resultant energy imbalance leads to weight gain (the excess energy is stored as body fat or adipose tissue) and also triggers numerous metabolic changes, alterations in the chemical processes that convert food into the energy and various substances needed to support life. These obesity-related metabolic changes increase a person's risk of developing adverse health conditions such as diabetes, a condition in which dangerously high levels of sugar from food accumulate in the blood.
Why Was This Study Done?
The changes in human fat in obesity have not been completely understood, although the abnormal metabolism of adipose tissue is increasingly seen as playing a critical part in excessive weight gain. It has been very difficult to decipher which molecular and metabolic changes associated with obesity are the result of becoming obese, and which might contribute towards the acquisition of obesity in humans in the first place. To discover more about the influence of environment on obesity-induced metabolic changes, the researchers in this study have investigated these changes in pairs of genetically identical twins.
What Did the Researchers Do and Find?
The researchers recruited 14 pairs of genetically identical Finnish twins born between 1975 and 1979 who were “obesity discordant”—that is, one twin of each pair had a BMI of about 25 (not obese); the other had a BMI of about 30 (obese). The researchers took fat and blood samples from each twin, determined the insulin sensitivity of each, and measured the body composition and various fat stores of each. They found that the obese twins had more subcutaneous, intra-abdominal, and liver fat and were less insulin sensitive than the non-obese twins. Insulin sensitivity correlated with the amount of liver fat. Analysis of gene expression in the fat samples showed that 19 gene pathways (mainly inflammatory pathways) were expressed more strongly (up-regulated) in the obese twins than the non-obese twins, whereas seven pathways were down-regulated. The most highly down-regulated pathway was a mitochondrial pathway involved in amino acid breakdown, but mitochondrial energy metabolism pathways were also down-regulated. Finally, mitochondrial DNA copy number in fat was reduced in the obese twins by nearly half, a novel observation that could partly account for the obesity-induced metabolic defects of these individuals.
What Do These Findings Mean?
These and other findings identify several pathways that are involved in the development of obesity and insulin resistance. In particular, they suggest that changes in mitochondrial energy production pathways and in mitochondrial amino acid metabolism pathways could play important roles in the development of obesity and of insulin resistance and in the accumulation of liver fat even in young obese people. The study design involving identical twins has here produced some evidence for aberrations in molecules critical for acquired obesity. The results suggest that careful management of obesity by lifestyle changes has the potential to correct the obesity-related metabolic changes in fat that would otherwise lead to diabetes and other adverse health conditions in obese individuals. In addition, they suggest that the development of therapies designed to correct mitochondrial metabolism might help to reduce the illnesses associated with obesity.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050051.
The MedlinePlus encyclopedia has pages on obesity and diabetes (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of obesity (in English and Spanish)
The UK National Health Service's health Web site (NHS Direct) provides information about obesity
The International Obesity Taskforce provides information about preventing obesity and on diabetes and obesity
The UK Foods Standards Agency and the United States Department of Agriculture provide online tools and useful advice about healthy eating for adults and children
Information is available for patients and carers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance
doi:10.1371/journal.pmed.0050051
PMCID: PMC2265758  PMID: 18336063
21.  Physical inactivity and obesity: A vicious circle 
Obesity (Silver Spring, Md.)  2008;16(2):409-414.
Objective
Physical activity (PA) begins to decline in adolescence with concomitant increase in weight. We hypothesized that a vicious circle may arise between decreasing physical activity and weight gain from adolescence to early adulthood.
Research Methods and Procedures
PA and self-perceived physical fitness assessed in adolescence (16-18 years) were used to predict the development of obesity (BMI≥30 kg/m2) and abdominal obesity (waist≥88 cm in females and ≥102 cm in males) at age 25 in 4240 twin individuals (90% of twins born in Finland 1975-1979). Ten 25-year-old monozygotic (MZ) twin pairs discordant for obesity (16 kg weight difference) were then carefully evaluated for current PA (triaxial accelerometer), total energy expenditure (TEE, doubly labeled water), and basal metabolic rate (BMR, indirect calorimetry).
Results
Physical inactivity in adolescence strongly predicted the risk of obesity (OR 3.9, 95%CI 1.4-10.9) and abdominal obesity (4.8, 1.9-12.0) at age 25, even after adjusting for baseline and current BMI. Poor physical fitness in adolescence also increased the risk of overall (5.1, 2.0-12.7) and abdominal obesity (3.2, 1.5-6.7) in adulthood. Physical inactivity was both causative and secondary to the development of obesity discordance in the MZ pairs. TEE did not differ between the MZ co-twins. PA levels were lower whereas BMR was higher in the obese co-twins.
Discussion
Physical inactivity in adolescence strongly and independently predicts total and especially abdominal obesity in young adulthood, favoring the development of a self-perpetuating vicious circle of obesity and physical inactivity. Physical (in)activity should be a major target of obesity prevention in the young.
doi:10.1038/oby.2007.72
PMCID: PMC2249563  PMID: 18239652
longitudinal; twin studies; body mass index; waist circumference; energy expenditure
22.  Acquired Obesity Is Associated with Changes in the Serum Lipidomic Profile Independent of Genetic Effects – A Monozygotic Twin Study 
PLoS ONE  2007;2(2):e218.
Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ) twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference) and ten weight concordant control pairs aged 24–27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat) and by MRI (subcutaneous and intra-abdominal fat). Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance.
doi:10.1371/journal.pone.0000218
PMCID: PMC1789242  PMID: 17299598

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