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1.  Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity 
Human Molecular Genetics  2013;22(13):2735-2747.
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10−8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
doi:10.1093/hmg/ddt104
PMCID: PMC3674797  PMID: 23449627
2.  Common variants at 12q15 and 12q24 are associated with infant head circumference 
Taal, H Rob | Pourcain, Beate St | Thiering, Elisabeth | Das, Shikta | Mook-Kanamori, Dennis O | Warrington, Nicole M | Kaakinen, Marika | Kreiner-Møller, Eskil | Bradfield, Jonathan P | Freathy, Rachel M | Geller, Frank | Guxens, Mònica | Cousminer, Diana L | Kerkhof, Marjan | Timpson, Nicholas J | Ikram, M Arfan | Beilin, Lawrence J | Bønnelykke, Klaus | Buxton, Jessica L | Charoen, Pimphen | Chawes, Bo Lund Krogsgaard | Eriksson, Johan | Evans, David M | Hofman, Albert | Kemp, John P | Kim, Cecilia E | Klopp, Norman | Lahti, Jari | Lye, Stephen J | McMahon, George | Mentch, Frank D | Müller, Martina | O’Reilly, Paul F | Prokopenko, Inga | Rivadeneira, Fernando | Steegers, Eric A P | Sunyer, Jordi | Tiesler, Carla | Yaghootkar, Hanieh | Breteler, Monique M B | Debette, Stephanie | Fornage, Myriam | Gudnason, Vilmundur | Launer, Lenore J | van der Lugt, Aad | Mosley, Thomas H | Seshadri, Sudha | Smith, Albert V | Vernooij, Meike W | Blakemore, Alexandra IF | Chiavacci, Rosetta M | Feenstra, Bjarke | Fernandez-Benet, Julio | Grant, Struan F A | Hartikainen, Anna-Liisa | van der Heijden, Albert J | Iñiguez, Carmen | Lathrop, Mark | McArdle, Wendy L | Mølgaard, Anne | Newnham, John P | Palmer, Lyle J | Palotie, Aarno | Pouta, Annneli | Ring, Susan M | Sovio, Ulla | Standl, Marie | Uitterlinden, Andre G | Wichmann, H-Erich | Vissing, Nadja Hawwa | DeCarli, Charles | van Duijn, Cornelia M | McCarthy, Mark I | Koppelman, Gerard H. | Estivill, Xavier | Hattersley, Andrew T | Melbye, Mads | Bisgaard, Hans | Pennell, Craig E | Widen, Elisabeth | Hakonarson, Hakon | Smith, George Davey | Heinrich, Joachim | Jarvelin, Marjo-Riitta | Jaddoe, Vincent W V
Nature genetics  2012;44(5):532-538.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
doi:10.1038/ng.2238
PMCID: PMC3773913  PMID: 22504419
3.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 
Horikoshi, Momoko | Yaghootkar, Hanieh | Mook-Kanamori, Dennis O. | Sovio, Ulla | Taal, H. Rob | Hennig, Branwen J. | Bradfield, Jonathan P. | St. Pourcain, Beate | Evans, David M. | Charoen, Pimphen | Kaakinen, Marika | Cousminer, Diana L. | Lehtimäki, Terho | Kreiner-Møller, Eskil | Warrington, Nicole M. | Bustamante, Mariona | Feenstra, Bjarke | Berry, Diane J. | Thiering, Elisabeth | Pfab, Thiemo | Barton, Sheila J. | Shields, Beverley M. | Kerkhof, Marjan | van Leeuwen, Elisabeth M. | Fulford, Anthony J. | Kutalik, Zoltán | Zhao, Jing Hua | den Hoed, Marcel | Mahajan, Anubha | Lindi, Virpi | Goh, Liang-Kee | Hottenga, Jouke-Jan | Wu, Ying | Raitakari, Olli T. | Harder, Marie N. | Meirhaeghe, Aline | Ntalla, Ioanna | Salem, Rany M. | Jameson, Karen A. | Zhou, Kaixin | Monies, Dorota M. | Lagou, Vasiliki | Kirin, Mirna | Heikkinen, Jani | Adair, Linda S. | Alkuraya, Fowzan S. | Al-Odaib, Ali | Amouyel, Philippe | Andersson, Ehm Astrid | Bennett, Amanda J. | Blakemore, Alexandra I.F. | Buxton, Jessica L. | Dallongeville, Jean | Das, Shikta | de Geus, Eco J. C. | Estivill, Xavier | Flexeder, Claudia | Froguel, Philippe | Geller, Frank | Godfrey, Keith M. | Gottrand, Frédéric | Groves, Christopher J. | Hansen, Torben | Hirschhorn, Joel N. | Hofman, Albert | Hollegaard, Mads V. | Hougaard, David M. | Hyppönen, Elina | Inskip, Hazel M. | Isaacs, Aaron | Jørgensen, Torben | Kanaka-Gantenbein, Christina | Kemp, John P. | Kiess, Wieland | Kilpeläinen, Tuomas O. | Klopp, Norman | Knight, Bridget A. | Kuzawa, Christopher W. | McMahon, George | Newnham, John P. | Niinikoski, Harri | Oostra, Ben A. | Pedersen, Louise | Postma, Dirkje S. | Ring, Susan M. | Rivadeneira, Fernando | Robertson, Neil R. | Sebert, Sylvain | Simell, Olli | Slowinski, Torsten | Tiesler, Carla M.T. | Tönjes, Anke | Vaag, Allan | Viikari, Jorma S. | Vink, Jacqueline M. | Vissing, Nadja Hawwa | Wareham, Nicholas J. | Willemsen, Gonneke | Witte, Daniel R. | Zhang, Haitao | Zhao, Jianhua | Wilson, James F. | Stumvoll, Michael | Prentice, Andrew M. | Meyer, Brian F. | Pearson, Ewan R. | Boreham, Colin A.G. | Cooper, Cyrus | Gillman, Matthew W. | Dedoussis, George V. | Moreno, Luis A | Pedersen, Oluf | Saarinen, Maiju | Mohlke, Karen L. | Boomsma, Dorret I. | Saw, Seang-Mei | Lakka, Timo A. | Körner, Antje | Loos, Ruth J.F. | Ong, Ken K. | Vollenweider, Peter | van Duijn, Cornelia M. | Koppelman, Gerard H. | Hattersley, Andrew T. | Holloway, John W. | Hocher, Berthold | Heinrich, Joachim | Power, Chris | Melbye, Mads | Guxens, Mònica | Pennell, Craig E. | Bønnelykke, Klaus | Bisgaard, Hans | Eriksson, Johan G. | Widén, Elisabeth | Hakonarson, Hakon | Uitterlinden, André G. | Pouta, Anneli | Lawlor, Debbie A. | Smith, George Davey | Frayling, Timothy M. | McCarthy, Mark I. | Grant, Struan F.A. | Jaddoe, Vincent W.V. | Jarvelin, Marjo-Riitta | Timpson, Nicholas J. | Prokopenko, Inga | Freathy, Rachel M.
Nature genetics  2012;45(1):76-82.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
doi:10.1038/ng.2477
PMCID: PMC3605762  PMID: 23202124
4.  Common variants at 6q22 and 17q21 are associated with intracranial volume 
Nature genetics  2012;44(5):539-544.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.
doi:10.1038/ng.2245
PMCID: PMC3618290  PMID: 22504418
5.  A Bivariate Genome-Wide Approach to Metabolic Syndrome 
Diabetes  2011;60(4):1329-1339.
OBJECTIVE
The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS.
RESEARCH DESIGN AND METHODS
Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected.
RESULTS
Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure.
CONCLUSIONS
Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
doi:10.2337/db10-1011
PMCID: PMC3064107  PMID: 21386085
6.  Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development 
PLoS Genetics  2011;7(2):e1001307.
An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10−20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10−23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (−0.40% (95% CI: −0.74, −0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (−4.72% (−5.81, −3.63), p = 10−17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.
Author Summary
Variation at the FTO locus is reliably associated with BMI and adiposity-related traits, but little is still known about the effects of variation at this gene, particularly in children. We have examined a large collection of samples for which both genotypes at rs9939609 and multiple measurements of BMI are available. We observe a positive association between the minor allele (A) at rs9939609 and BMI emerging in childhood that has the characteristics of a shift in the age scale leading simultaneously to lower BMI during infancy and higher BMI in childhood. Assessed in cross section and longitudinally, we find evidence of variation at rs9939609 being associated with the timing of AR and the concert of events expected with such a change to the BMI curve. Importantly, the apparently negative association between the minor allele (A) and BMI in early life, which is then followed by an earlier AR and greater BMI in childhood, is a pattern known to be associated with both the risk of adult BMI and metabolic disorders such as type 2 diabetes (T2D). These findings are important in our understanding of the contribution of FTO to adiposity, but also in light of efforts to appreciate genetic effects in a lifecourse context.
doi:10.1371/journal.pgen.1001307
PMCID: PMC3040655  PMID: 21379325
7.  Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight 
Freathy, Rachel M | Mook-Kanamori, Dennis O | Sovio, Ulla | Prokopenko, Inga | Timpson, Nicholas J | Berry, Diane J | Warrington, Nicole M | Widen, Elisabeth | Hottenga, Jouke Jan | Kaakinen, Marika | Lange, Leslie A | Bradfield, Jonathan P | Kerkhof, Marjan | Marsh, Julie A | Mägi, Reedik | Chen, Chih-Mei | Lyon, Helen N | Kirin, Mirna | Adair, Linda S | Aulchenko, Yurii S | Bennett, Amanda J | Borja, Judith B | Bouatia-Naji, Nabila | Charoen, Pimphen | Coin, Lachlan J M | Cousminer, Diana L | de Geus, Eco J. C. | Deloukas, Panos | Elliott, Paul | Evans, David M | Froguel, Philippe | Glaser, Beate | Groves, Christopher J | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hirschhorn, Joel N | Hofman, Albert | Holly, Jeff M P | Hyppönen, Elina | Kanoni, Stavroula | Knight, Bridget A | Laitinen, Jaana | Lindgren, Cecilia M | McArdle, Wendy L | O'Reilly, Paul F | Pennell, Craig E | Postma, Dirkje S | Pouta, Anneli | Ramasamy, Adaikalavan | Rayner, Nigel W | Ring, Susan M | Rivadeneira, Fernando | Shields, Beverley M | Strachan, David P | Surakka, Ida | Taanila, Anja | Tiesler, Carla | Uitterlinden, Andre G | van Duijn, Cornelia M | Wijga, Alet H | Willemsen, Gonneke | Zhang, Haitao | Zhao, Jianhua | Wilson, James F | Steegers, Eric A P | Hattersley, Andrew T | Eriksson, Johan G | Peltonen, Leena | Mohlke, Karen L | Grant, Struan F A | Hakonarson, Hakon | Koppelman, Gerard H | Dedoussis, George V | Heinrich, Joachim | Gillman, Matthew W | Palmer, Lyle J | Frayling, Timothy M | Boomsma, Dorret I | Smith, George Davey | Power, Chris | Jaddoe, Vincent W V | Jarvelin, Marjo-Riitta | McCarthy, Mark I
Nature genetics  2010;42(5):430-435.
INTRODUCTORY PARAGRAPH
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (N=10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in thirteen replication studies (N=27,591). Rs900400 near LEKR1 and CCNL1 (P=2×10−35), and rs9883204 in ADCY5 (P=7×10−15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and type 2 diabetes susceptibility,1 providing evidence that the well described association between lower birth weight and subsequent type 2 diabetes2,3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, the 9% of Europeans with 4 birth weight-lowering alleles were, on average, 113g (95%CI 89-137g) lighter at birth than the 24% with 0 or 1 allele (Ptrend=7×10−30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.4
doi:10.1038/ng.567
PMCID: PMC2862164  PMID: 20372150
8.  Life-Course Analysis of a Fat Mass and Obesity-Associated (FTO) Gene Variant and Body Mass Index in the Northern Finland Birth Cohort 1966 Using Structural Equation Modeling 
American Journal of Epidemiology  2010;172(6):653-665.
The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body mass index (BMI; weight (kg)/height (m)2) is well-replicated. More thorough analyses utilizing phenotypic data over the life course may deepen our understanding of the development of BMI and thus help in the prevention of obesity. The authors used a structural equation modeling approach to explore the network of variables associated with BMI from the prenatal period to age 31 years (1965–1997) in 4,435 subjects from the Northern Finland Birth Cohort 1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in the analyses without separate imputation steps, as well as differentiation between direct and indirect effects. There was an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years that persisted after controlling for several relevant factors during the life course. The total effect of the FTO variant on adult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects on earlier BMI development. In addition to well-established genetic determinants, many life-course factors such as physical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI.
doi:10.1093/aje/kwq178
PMCID: PMC2938267  PMID: 20702506
body mass index; molecular epidemiology; structural equation model
10.  Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy 
PLoS Genetics  2010;6(2):e1000856.
Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.
Author Summary
Genome-wide association studies have been used to identify genetic variants conferring susceptibility to diseases, intermediate phenotypes, and physiological traits such as height, hair color, and age at menarche. Here we analyze the NFBC1966 and ALSPAC birth cohorts to investigate the genetic determinants of a key developmental process: primary tooth development. The prospective nature of our studies allows us to exploit accurate measurements of age at first tooth eruption and number of teeth at one year, and also provides the opportunity to assess whether genetic variants affecting these traits are associated with dental problems later in the life course. Of the genes that we find to be associated with primary tooth development, several have established roles in tooth development and growth, and almost half have proposed links with the development of cancer. We find that one of the variants is also associated with occlusion defects requiring orthodontic treatment later in life. Our findings should provide a strong foundation for the study of the genetic architecture of tooth development, which as well as its relevance to medicine and dentistry, may have implications in evolutionary biology since teeth represent important markers of evolution.
doi:10.1371/journal.pgen.1000856
PMCID: PMC2829062  PMID: 20195514
11.  Genome-wide association analysis of metabolic traits in a birth cohort from a founder population 
Nature genetics  2008;41(1):35-46.
Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene-environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci.
doi:10.1038/ng.271
PMCID: PMC2687077  PMID: 19060910
12.  Genetic Determinants of Height Growth Assessed Longitudinally from Infancy to Adulthood in the Northern Finland Birth Cohort 1966 
PLoS Genetics  2009;5(3):e1000409.
Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N = 3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0–20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p = 0.0030) and for the SNP in HHIP (p = 0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.
Author Summary
Family studies have shown that adult height is largely genetically determined. Identification of common genetic factors has been expedited with recent advances in genotyping techniques. However, factors regulating childhood height growth remain unclear. We investigated genetic variants of adult height for associations with peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal growth spurt in a population based sample of 3,538 Finns born in 1966. Most variants studied associated with adult height in this sample. Of the 48 genetic variants tested, seven of them associated with PHV1 and five with PHV2. However, only one of these associated with both, and we found suggestive evidence for differential effects at different stages of growth for some of the variants. In this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2. However, these differences may reflect lower statistical power to detect associations with height velocities compared to adult height. This study provides a foundation for further biological investigation into the genes acting at each stage of height growth.
doi:10.1371/journal.pgen.1000409
PMCID: PMC2646138  PMID: 19266077
13.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity 
Science (New York, N.Y.)  2007;316(5826):889-894.
Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
doi:10.1126/science.1141634
PMCID: PMC2646098  PMID: 17434869
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.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk 
Dupuis, Josée | Langenberg, Claudia | Prokopenko, Inga | Saxena, Richa | Soranzo, Nicole | Jackson, Anne U | Wheeler, Eleanor | Glazer, Nicole L | Bouatia-Naji, Nabila | Gloyn, Anna L | Lindgren, Cecilia M | Mägi, Reedik | Morris, Andrew P | Randall, Joshua | Johnson, Toby | Elliott, Paul | Rybin, Denis | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Henneman, Peter | Grallert, Harald | Dehghan, Abbas | Hottenga, Jouke Jan | Franklin, Christopher S | Navarro, Pau | Song, Kijoung | Goel, Anuj | Perry, John R B | Egan, Josephine M | Lajunen, Taina | Grarup, Niels | Sparsø, Thomas | Doney, Alex | Voight, Benjamin F | Stringham, Heather M | Li, Man | Kanoni, Stavroula | Shrader, Peter | Cavalcanti-Proença, Christine | Kumari, Meena | Qi, Lu | Timpson, Nicholas J | Gieger, Christian | Zabena, Carina | Rocheleau, Ghislain | Ingelsson, Erik | An, Ping | O’Connell, Jeffrey | Luan, Jian'an | Elliott, Amanda | McCarroll, Steven A | Payne, Felicity | Roccasecca, Rosa Maria | Pattou, François | Sethupathy, Praveen | Ardlie, Kristin | Ariyurek, Yavuz | Balkau, Beverley | Barter, Philip | Beilby, John P | Ben-Shlomo, Yoav | Benediktsson, Rafn | Bennett, Amanda J | Bergmann, Sven | Bochud, Murielle | Boerwinkle, Eric | Bonnefond, Amélie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Bumpstead, Suzannah J | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter | Clarke, Robert | Coin, Lachlan J M | Cooper, Matthew N | Cornelis, Marilyn | Crawford, Gabe | Crisponi, Laura | Day, Ian N M | de Geus, Eco | Delplanque, Jerome | Dina, Christian | Erdos, Michael R | Fedson, Annette C | Fischer-Rosinsky, Antje | Forouhi, Nita G | Fox, Caroline S | Frants, Rune | Franzosi, Maria Grazia | Galan, Pilar | Goodarzi, Mark O | Graessler, Jürgen | Groves, Christopher J | Grundy, Scott | Gwilliam, Rhian | Gyllensten, Ulf | Hadjadj, Samy | Hallmans, Göran | Hammond, Naomi | Han, Xijing | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hayward, Caroline | Heath, Simon C | Hercberg, Serge | Herder, Christian | Hicks, Andrew A | Hillman, David R | Hingorani, Aroon D | Hofman, Albert | Hui, Jennie | Hung, Joe | Isomaa, Bo | Johnson, Paul R V | Jørgensen, Torben | Jula, Antti | Kaakinen, Marika | Kaprio, Jaakko | Kesaniemi, Y Antero | Kivimaki, Mika | Knight, Beatrice | Koskinen, Seppo | Kovacs, Peter | Kyvik, Kirsten Ohm | Lathrop, G Mark | Lawlor, Debbie A | Le Bacquer, Olivier | Lecoeur, Cécile | Li, Yun | Lyssenko, Valeriya | Mahley, Robert | Mangino, Massimo | Manning, Alisa K | Martínez-Larrad, María Teresa | McAteer, Jarred B | McCulloch, Laura J | McPherson, Ruth | Meisinger, Christa | Melzer, David | Meyre, David | Mitchell, Braxton D | Morken, Mario A | Mukherjee, Sutapa | Naitza, Silvia | Narisu, Narisu | Neville, Matthew J | Oostra, Ben A | Orrù, Marco | Pakyz, Ruth | Palmer, Colin N A | Paolisso, Giuseppe | Pattaro, Cristian | Pearson, Daniel | Peden, John F | Pedersen, Nancy L. | Perola, Markus | Pfeiffer, Andreas F H | Pichler, Irene | Polasek, Ozren | Posthuma, Danielle | Potter, Simon C | Pouta, Anneli | Province, Michael A | Psaty, Bruce M | Rathmann, Wolfgang | Rayner, Nigel W | Rice, Kenneth | Ripatti, Samuli | Rivadeneira, Fernando | Roden, Michael | Rolandsson, Olov | Sandbaek, Annelli | Sandhu, Manjinder | Sanna, Serena | Sayer, Avan Aihie | Scheet, Paul | Scott, Laura J | Seedorf, Udo | Sharp, Stephen J | Shields, Beverley | Sigurðsson, Gunnar | Sijbrands, Erik J G | Silveira, Angela | Simpson, Laila | Singleton, Andrew | Smith, Nicholas L | Sovio, Ulla | Swift, Amy | Syddall, Holly | Syvänen, Ann-Christine | Tanaka, Toshiko | Thorand, Barbara | Tichet, Jean | Tönjes, Anke | Tuomi, Tiinamaija | Uitterlinden, André G | van Dijk, Ko Willems | van Hoek, Mandy | Varma, Dhiraj | Visvikis-Siest, Sophie | Vitart, Veronique | Vogelzangs, Nicole | Waeber, Gérard | Wagner, Peter J | Walley, Andrew | Walters, G Bragi | Ward, Kim L | Watkins, Hugh | Weedon, Michael N | Wild, Sarah H | Willemsen, Gonneke | Witteman, Jaqueline C M | Yarnell, John W G | Zeggini, Eleftheria | Zelenika, Diana | Zethelius, Björn | Zhai, Guangju | Zhao, Jing Hua | Zillikens, M Carola | Borecki, Ingrid B | Loos, Ruth J F | Meneton, Pierre | Magnusson, Patrik K E | Nathan, David M | Williams, Gordon H | Hattersley, Andrew T | Silander, Kaisa | Salomaa, Veikko | Smith, George Davey | Bornstein, Stefan R | Schwarz, Peter | Spranger, Joachim | Karpe, Fredrik | Shuldiner, Alan R | Cooper, Cyrus | Dedoussis, George V | Serrano-Ríos, Manuel | Morris, Andrew D | Lind, Lars | Palmer, Lyle J | Hu, Frank B. | Franks, Paul W | Ebrahim, Shah | Marmot, Michael | Kao, W H Linda | Pankow, James S | Sampson, Michael J | Kuusisto, Johanna | Laakso, Markku | Hansen, Torben | Pedersen, Oluf | Pramstaller, Peter Paul | Wichmann, H Erich | Illig, Thomas | Rudan, Igor | Wright, Alan F | Stumvoll, Michael | Campbell, Harry | Wilson, James F | Hamsten, Anders | Bergman, Richard N | Buchanan, Thomas A | Collins, Francis S | Mohlke, Karen L | Tuomilehto, Jaakko | Valle, Timo T | Altshuler, David | Rotter, Jerome I | Siscovick, David S | Penninx, Brenda W J H | Boomsma, Dorret | Deloukas, Panos | Spector, Timothy D | Frayling, Timothy M | Ferrucci, Luigi | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | van Duijn, Cornelia M | Aulchenko, Yurii S | Cao, Antonio | Scuteri, Angelo | Schlessinger, David | Uda, Manuela | Ruokonen, Aimo | Jarvelin, Marjo-Riitta | Waterworth, Dawn M | Vollenweider, Peter | Peltonen, Leena | Mooser, Vincent | Abecasis, Goncalo R | Wareham, Nicholas J | Sladek, Robert | Froguel, Philippe | Watanabe, Richard M | Meigs, James B | Groop, Leif | Boehnke, Michael | McCarthy, Mark I | Florez, Jose C | Barroso, Inês
Nature genetics  2010;42(2):105-116.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
doi:10.1038/ng.520
PMCID: PMC3018764  PMID: 20081858

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