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1.  Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin 
PLoS Genetics  2014;10(7):e1004474.
Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
Author Summary
Cortisol is a steroid hormone from the adrenal glands that is essential in the response to stress. Most cortisol in blood is bound to corticosteroid binding globulin (CBG). Diseases causing cortisol deficiency (Addison's disease) or excess (Cushing's syndrome) are life-threatening. Variations in plasma cortisol have been associated with cardiovascular and psychiatric diseases and their risk factors. To dissect the genetic contribution to variation in plasma cortisol, we formed the CORtisol NETwork (CORNET) consortium and recruited collaborators with suitable samples from more than 15,000 people. The results reveal that the major genetic influence on plasma cortisol is mediated by variations in the binding capacity of CBG. This is determined by differences in the circulating concentrations of CBG and also in the immunoreactivity of its ‘reactive centre loop’, potentially influencing not only binding affinity for cortisol but also the stability of CBG and hence the tissue delivery of cortisol. These findings provide the first evidence for a common genetic effect on levels of this clinically important hormone, suggest that differences in CBG between individuals are biologically important, and pave the way for further research to dissect causality in the associations of plasma cortisol with common diseases.
doi:10.1371/journal.pgen.1004474
PMCID: PMC4091794  PMID: 25010111
2.  Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment 
PLoS Genetics  2014;10(6):e1004423.
Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20–0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n∼9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10−37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10−14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10−10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
Author Summary
The heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To investigate whether the genes underlying bone acquisition act in a site-specific manner, we quantified the shared genetic influences across axial and appendicular skeletal sites by estimating the genetic and residual correlation of BMD at the upper limb, lower limb and the skull. Our results suggest that different skeletal sites as measured by total-body Dual-Energy X-Ray Absorptiometry are to a certain extent under distinct genetic and environmental influences. To further explore the basis for these differences, genome-wide association meta-analyses were performed to identify genetic loci that are preferentially associated with one or more skeletal regions. Variants at 13 loci (including RIN3, a novel BMD associated locus) reached genome-wide significance and several displayed evidence of differential association with BMD across the different skeletal sites in particular CPED1 and WNT16. Our results suggest that it may be advantageous to decompose the total-body BMD measures and perform GWAS at separate skeletal regions. By allowing for site-specific differences, new genetic variants affecting BMD and future risk of osteoporosis may be uncovered.
doi:10.1371/journal.pgen.1004423
PMCID: PMC4063697  PMID: 24945404
3.  Genome-wide meta-analysis identifies new susceptibility loci for migraine 
Anttila, Verneri | Winsvold, Bendik S. | Gormley, Padhraig | Kurth, Tobias | Bettella, Francesco | McMahon, George | Kallela, Mikko | Malik, Rainer | de Vries, Boukje | Terwindt, Gisela | Medland, Sarah E. | Todt, Unda | McArdle, Wendy L. | Quaye, Lydia | Koiranen, Markku | Ikram, M. Arfan | Lehtimäki, Terho | Stam, Anine H. | Ligthart, Lannie | Wedenoja, Juho | Dunham, Ian | Neale, Benjamin M. | Palta, Priit | Hamalainen, Eija | Schürks, Markus | Rose, Lynda M | Buring, Julie E. | Ridker, Paul M. | Steinberg, Stacy | Stefansson, Hreinn | Jakobsson, Finnbogi | Lawlor, Debbie A. | Evans, David M. | Ring, Susan M. | Färkkilä, Markus | Artto, Ville | Kaunisto, Mari A | Freilinger, Tobias | Schoenen, Jean | Frants, Rune R. | Pelzer, Nadine | Weller, Claudia M. | Zielman, Ronald | Heath, Andrew C. | Madden, Pamela A.F. | Montgomery, Grant W. | Martin, Nicholas G. | Borck, Guntram | Göbel, Hartmut | Heinze, Axel | Heinze-Kuhn, Katja | Williams, Frances M.K. | Hartikainen, Anna-Liisa | Pouta, Anneli | van den Ende, Joyce | Uitterlinden, Andre G. | Hofman, Albert | Amin, Najaf | Hottenga, Jouke-Jan | Vink, Jacqueline M. | Heikkilä, Kauko | Alexander, Michael | Muller-Myhsok, Bertram | Schreiber, Stefan | Meitinger, Thomas | Wichmann, Heinz Erich | Aromaa, Arpo | Eriksson, Johan G. | Traynor, Bryan | Trabzuni, Daniah | Rossin, Elizabeth | Lage, Kasper | Jacobs, Suzanne B.R. | Gibbs, J. Raphael | Birney, Ewan | Kaprio, Jaakko | Penninx, Brenda W. | Boomsma, Dorret I. | van Duijn, Cornelia | Raitakari, Olli | Jarvelin, Marjo-Riitta | Zwart, John-Anker | Cherkas, Lynn | Strachan, David P. | Kubisch, Christian | Ferrari, Michel D. | van den Maagdenberg, Arn M.J.M. | Dichgans, Martin | Wessman, Maija | Smith, George Davey | Stefansson, Kari | Daly, Mark J. | Nyholt, Dale R. | Chasman, Daniel | Palotie, Aarno
Nature genetics  2013;45(8):912-917.
doi:10.1038/ng.2676
PMCID: PMC4041123  PMID: 23793025
4.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
doi:10.1038/ng.2610
PMCID: PMC3696959  PMID: 23583979
5.  Personality, Behavior and Environmental Features Associated with OXTR Genetic Variants in British Mothers 
PLoS ONE  2014;9(3):e90465.
Background
It is assumed that the oxytocin receptor gene (OXTR) is associated with factors that are related to features of reproduction as well as the currently emerging fields of mood and emotional response.
Methods
We analysed data from over 8000 mothers who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC). We determined reproductive, emotional and personality differences related to the two SNPs rs53576 and rs2254298 of the oxytocin receptor gene to determine whether there was evidence in this population for: (i) associations with emotional and personality differences, and (ii) behavioural or environmental links with these SNPs using a hypothesis free approach with over 1000 types of exposure.
Results
Our analyses of 7723 women showed that there were no differences in 11 mood, social or relationship characteristics associated with the rs2254298, and just one with rs53576 (with emotional loneliness) – one statistically significant out of 22 tests is no more than would be expected by chance. There were no interactions with childhood abuse. Using a hypothesis-free approach we found few indicators of environmental or behavioural differences associated with rs2254298, but there was an excess of associations with eating habits with rs53576. The findings included an association with dieting to lose weight, and habits typical of bulimia for the women with GG. The nutrition of the women also showed negative associations of the GG genotype with 13 nutrients, including vitamins D, B12 and retinol, and intake of calcium, potassium and iodine.
Conclusions
We conclude that this large database of pregnant women was unable to provide confirmation of the types of personality associated with these two OXTR SNPs, but we have shown some evidence of eating differences in those with GG on rs53576. Confirmation of our hypothesis free associations using other data sets is important.
doi:10.1371/journal.pone.0090465
PMCID: PMC3951216  PMID: 24621820
6.  Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence 
Molecular Autism  2014;5:18.
Background
Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence.
Methods
Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).
Results
GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10−9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10−8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007).
Conclusions
Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.
doi:10.1186/2040-2392-5-18
PMCID: PMC3940728  PMID: 24564958
ALSPAC; ASD; Autism; GCTA heritability; GWAS; Social communication
7.  Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ 
Human Genetics  2014;133:869-881.
Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI—and their associated deficits—are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-014-1427-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-014-1427-3
PMCID: PMC4053598  PMID: 24509779
9.  Prenatal alcohol exposure and childhood atopic disease: A Mendelian randomization approach☆ 
Background
Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations are likely to be confounded.
Objective
We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding.
Methods
In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol).
Results
After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio [OR] per category increase in intake: 0.91 [95% CI, 0.82-1.01] and 0.87 [95% CI, 0.78-0.98], respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 [95% CI, 0.66-1.47]) or hay fever (OR, 1.11 [95% CI, 0.71-1.72]), nor with any other atopic outcome.
Conclusion
We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood.
doi:10.1016/j.jaci.2013.04.051
PMCID: PMC3884122  PMID: 23806636
Alcohol; ADH1B; Mendelian randomization; prenatal exposure; ALSPAC; pregnancy; birth cohort; asthma; atopy; ADH, Alcohol dehydrogenase; ALSPAC, Avon Longitudinal Study of Parents and Children (ALSPAC); GWAS, Genome Wide Association Study; PCA, Principal Components Analysis
10.  Vitamin D Status Is Not Associated with Outcomes of Experimentally-Induced Muscle Weakness and Pain in Young, Healthy Volunteers 
Vitamin D receptors have been identified in skeletal muscle; and symptoms of vitamin D deficiency include muscle weakness and pain. Moreover, increased serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with improved muscle function. To further clarify the importance of vitamin D to muscle, we examined the association between vitamin D status and exercise-induced muscle pain and weakness in healthy people. Muscle damage to the elbow flexors was induced with eccentric exercise (EE) in 48 individuals (22.5 ± 3.2 yrs). Muscle pain ratings following unloaded movement and peak isometric force (IF) were collected before EE and for 4 days post-EE. Linear regression was used to determine if serum 25(OH)D was a predictor of any outcome. In males, R2-values from 0.48 to 1.00. R2 for IF ranged from 0 to 0.02 and P-values from 0.48 to 1.00. In females, R2 for pain ratings ranged from 0.01 to 0.11 and P-values from 0.14 to 0.59. R2 for IF ranged from 0 to 0.04 and P-values from 0.41 to 0.90. In conclusion, vitamin D status did not predict muscle pain or strength after EE-induced muscle damage in young healthy men and women.
doi:10.1155/2010/674240
PMCID: PMC3010688  PMID: 21209718
11.  Common variation contributes to the genetic architecture of social communication traits 
Molecular Autism  2013;4:34.
Background
Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype.
Methods
We performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364).
Results
Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009
Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027).
Conclusion
Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
doi:10.1186/2040-2392-4-34
PMCID: PMC3853437  PMID: 24047820
ALSPAC; RAINE; Autistic trait; GWAS; Social communication; Association
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
PLoS Genetics  2013;9(9):e1003751.
Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10−9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Author Summary
Humans have developed a population level bias towards right-handedness for tool-use. Understanding the genetic basis of handedness can help explain why this bias exists and may offer clues into the evolution of handedness and brain asymmetry. We have tested for correlation between relative hand skill and hundreds of thousands of genetic variants in a cohort of individuals with reading disability. The strongest associated variant is in the gene PCSK6, an enzyme that cleaves NODAL into an active form. NODAL plays a key role during the establishment of left/right (LR) asymmetry in diverse species, from snails to mammals. Pcsk6 knock-out mice display LR asymmetry defects like heterotaxia (abnormal organ positioning). We uncovered further variants associated with relative hand skill in the human versions of genes that also cause the LR asymmetry phenotypes heterotaxia, and situs inversus (reversal of organ asymmetry) when knocked out in mice. These results replicate in an independent general population cohort without reading disability. We propose that handedness is under the control of many variants, some of which are in genes that also contribute to the determination of body LR asymmetry.
doi:10.1371/journal.pgen.1003751
PMCID: PMC3772043  PMID: 24068947
Purpose.
To examine the extent to which the two major determinants of refractive error, corneal curvature and axial length, are scaled relative to one another by shared genetic variants, along with their relationship to the genetic scaling of height.
Methods.
Corneal curvature, axial length, and height were measured in unrelated 14- to 17-year-old white European participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 1915) and in unrelated 40- to 80-year-old participants of the Singapore Chinese Eye Study (SCES; n = 1642). Univariate and bivariate heritability analyses were performed with methods that avoid confounding by common family environment, using information solely from genome-wide high-density genotypes.
Results.
In ALSPAC subjects, axial length, corneal curvature, and height had similar lower-bound heritability estimates: axial length, h2 = 0.46 (SE = 0.16, P = 0.002); corneal curvature, h2 = 0.42 (SE = 0.16, P = 0.004); height, h2 = 0.48 (SE = 0.17, P = 0.002). The corresponding estimates in the SCES were 0.79 (SE = 0.18, P < 0.001), 0.35 (SE = 0.20, P = 0.036), and 0.31 (SE = 0.20, P = 0.061), respectively. The genetic correlation between corneal curvature and axial length was 0.69 (SE = 0.17, P = 0.019) for ALSPAC participants and 0.64 (SE = 0.22, P = 0.003) for SCES participants. In the subset of 1478 emmetropic ALSPAC individuals, the genetic correlation was 0.85 (SE = 0.12, P = 0.008).
Conclusions.
These results imply that coordinated scaling of ocular component dimensions is largely achieved by hundreds to thousands of common genetic variants, each with a small pleiotropic effect. Furthermore, genome-wide association studies (GWAS) for either axial length or corneal curvature are likely to identify variants controlling overall eye size when using discovery cohorts dominated by emmetropes, but trait-specific variants in discovery cohorts dominated by ametropes.
Analyses of high-density genetic markers distributed across the genomes of 1915 European teenagers and 1642 Chinese adults suggested that commonly occurring, additively acting genetic variants largely codetermine corneal curvature and axial length, especially in emmetropes.
doi:10.1167/iovs.12-10560
PMCID: PMC3626516  PMID: 23385790
Rietveld, Cornelius A. | Medland, Sarah E. | Derringer, Jaime | Yang, Jian | Esko, Tõnu | Martin, Nicolas W. | Westra, Harm-Jan | Shakhbazov, Konstantin | Abdellaoui, Abdel | Agrawal, Arpana | Albrecht, Eva | Alizadeh, Behrooz Z. | Amin, Najaf | Barnard, John | Baumeister, Sebastian E. | Benke, Kelly S. | Bielak, Lawrence F. | Boatman, Jeffrey A. | Boyle, Patricia A. | Davies, Gail | de Leeuw, Christiaan | Eklund, Niina | Evans, Daniel S. | Ferhmann, Rudolf | Fischer, Krista | Gieger, Christian | Gjessing, Håkon K. | Hägg, Sara | Harris, Jennifer R. | Hayward, Caroline | Holzapfel, Christina | Ibrahim-Verbaas, Carla A. | Ingelsson, Erik | Jacobsson, Bo | Joshi, Peter K. | Jugessur, Astanand | Kaakinen, Marika | Kanoni, Stavroula | Karjalainen, Juha | Kolcic, Ivana | Kristiansson, Kati | Kutalik, Zoltán | Lahti, Jari | Lee, Sang H. | Lin, Peng | Lind, Penelope A. | Liu, Yongmei | Lohman, Kurt | Loitfelder, Marisa | McMahon, George | Vidal, Pedro Marques | Meirelles, Osorio | Milani, Lili | Myhre, Ronny | Nuotio, Marja-Liisa | Oldmeadow, Christopher J. | Petrovic, Katja E. | Peyrot, Wouter J. | Polašek, Ozren | Quaye, Lydia | Reinmaa, Eva | Rice, John P. | Rizzi, Thais S. | Schmidt, Helena | Schmidt, Reinhold | Smith, Albert V. | Smith, Jennifer A. | Tanaka, Toshiko | Terracciano, Antonio | van der Loos, Matthijs J.H.M. | Vitart, Veronique | Völzke, Henry | Wellmann, Jürgen | Yu, Lei | Zhao, Wei | Allik, Jüri | Attia, John R. | Bandinelli, Stefania | Bastardot, François | Beauchamp, Jonathan | Bennett, David A. | Berger, Klaus | Bierut, Laura J. | Boomsma, Dorret I. | Bültmann, Ute | Campbell, Harry | Chabris, Christopher F. | Cherkas, Lynn | Chung, Mina K. | Cucca, Francesco | de Andrade, Mariza | De Jager, Philip L. | De Neve, Jan-Emmanuel | Deary, Ian J. | Dedoussis, George V. | Deloukas, Panos | Dimitriou, Maria | Eiriksdottir, Gudny | Elderson, Martin F. | Eriksson, Johan G. | Evans, David M. | Faul, Jessica D. | Ferrucci, Luigi | Garcia, Melissa E. | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Per | Harris, Juliette M. | Harris, Tamara B. | Hastie, Nicholas D. | Heath, Andrew C. | Hernandez, Dena G. | Hoffmann, Wolfgang | Hofman, Adriaan | Holle, Rolf | Holliday, Elizabeth G. | Hottenga, Jouke-Jan | Iacono, William G. | Illig, Thomas | Järvelin, Marjo-Riitta | Kähönen, Mika | Kaprio, Jaakko | Kirkpatrick, Robert M. | Kowgier, Matthew | Latvala, Antti | Launer, Lenore J. | Lawlor, Debbie A. | Lehtimäki, Terho | Li, Jingmei | Lichtenstein, Paul | Lichtner, Peter | Liewald, David C. | Madden, Pamela A. | Magnusson, Patrik K. E. | Mäkinen, Tomi E. | Masala, Marco | McGue, Matt | Metspalu, Andres | Mielck, Andreas | Miller, Michael B. | Montgomery, Grant W. | Mukherjee, Sutapa | Nyholt, Dale R. | Oostra, Ben A. | Palmer, Lyle J. | Palotie, Aarno | Penninx, Brenda | Perola, Markus | Peyser, Patricia A. | Preisig, Martin | Räikkönen, Katri | Raitakari, Olli T. | Realo, Anu | Ring, Susan M. | Ripatti, Samuli | Rivadeneira, Fernando | Rudan, Igor | Rustichini, Aldo | Salomaa, Veikko | Sarin, Antti-Pekka | Schlessinger, David | Scott, Rodney J. | Snieder, Harold | Pourcain, Beate St | Starr, John M. | Sul, Jae Hoon | Surakka, Ida | Svento, Rauli | Teumer, Alexander | Tiemeier, Henning | Rooij, Frank JAan | Van Wagoner, David R. | Vartiainen, Erkki | Viikari, Jorma | Vollenweider, Peter | Vonk, Judith M. | Waeber, Gérard | Weir, David R. | Wichmann, H.-Erich | Widen, Elisabeth | Willemsen, Gonneke | Wilson, James F. | Wright, Alan F. | Conley, Dalton | Davey-Smith, George | Franke, Lude | Groenen, Patrick J. F. | Hofman, Albert | Johannesson, Magnus | Kardia, Sharon L.R. | Krueger, Robert F. | Laibson, David | Martin, Nicholas G. | Meyer, Michelle N. | Posthuma, Danielle | Thurik, A. Roy | Timpson, Nicholas J. | Uitterlinden, André G. | van Duijn, Cornelia M. | Visscher, Peter M. | Benjamin, Daniel J. | Cesarini, David | Koellinger, Philipp D.
Science (New York, N.Y.)  2013;340(6139):1467-1471.
A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
doi:10.1126/science.1235488
PMCID: PMC3751588  PMID: 23722424
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
Human Molecular Genetics  2013;22(18):3807-3817.
Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10−8) for ‘age at first tooth’ and 11 loci for ‘number of teeth’. Together, these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
doi:10.1093/hmg/ddt231
PMCID: PMC3749866  PMID: 23704328
PLoS ONE  2013;8(5):e63762.
Language impairment (LI) and reading disability (RD) are common pediatric neurobehavioral disorders that frequently co-occur, suggesting they share etiological determinants. Recently, our group identified prenatal nicotine exposure as a factor for RD and poor reading performance. Using smoking questionnaire and language data from the Avon Longitudinal Study of Parents and Children, we first determined if this risk could be expanded to other communication disorders by evaluating whether prenatal nicotine exposure increases risk for LI and poor performance on language tasks. Prenatal nicotine exposure increased LI risk (OR = 1.60; p = 0.0305) in a dose-response fashion with low (OR = 1.25; p = 0.1202) and high (OR = 3.84; p = 0.0002) exposures. Next, hypothesizing that the effects of prenatal nicotine may also implicate genes that function in nicotine related pathways, we determined whether known nicotine dependence (ND) genes associate with performance on language tasks. We assessed the association of 33 variants previously implicated in ND with LI and language abilities, finding association between ANKK1/DRD2 and performance on language tasks (p≤0.0003). The associations of markers within ANKK1 were replicated in a separate LI case-control cohort (p<0.05). Our results show that smoking during pregnancy increases the risk for LI and poor performance on language tasks and that ANKK1/DRD2 contributes to language performance. More precisely, these findings suggest that prenatal environmental factors influence in utero development of neural circuits vital to language. Our association of ANKK1/DRD2 further implicates the role of nicotine-related pathways and dopamine signaling in language processing, particularly in comprehension and phonological memory.
doi:10.1371/journal.pone.0063762
PMCID: PMC3655151  PMID: 23691092
van der Harst, Pim | Zhang, Weihua | Leach, Irene Mateo | Rendon, Augusto | Verweij, Niek | Sehmi, Joban | Paul, Dirk S. | Elling, Ulrich | Allayee, Hooman | Li, Xinzhong | Radhakrishnan, Aparna | Tan, Sian-Tsung | Voss, Katrin | Weichenberger, Christian X. | Albers, Cornelis A. | Al-Hussani, Abtehale | Asselbergs, Folkert W. | Ciullo, Marina | Danjou, Fabrice | Dina, Christian | Esko, Tõnu | Evans, David M. | Franke, Lude | Gögele, Martin | Hartiala, Jaana | Hersch, Micha | Holm, Hilma | Hottenga, Jouke-Jan | Kanoni, Stavroula | Kleber, Marcus E. | Lagou, Vasiliki | Langenberg, Claudia | Lopez, Lorna M. | Lyytikäinen, Leo-Pekka | Melander, Olle | Murgia, Federico | Nolte, Ilja M. | O’Reilly, Paul F. | Padmanabhan, Sandosh | Parsa, Afshin | Pirastu, Nicola | Porcu, Eleonora | Portas, Laura | Prokopenko, Inga | Ried, Janina S. | Shin, So-Youn | Tang, Clara S. | Teumer, Alexander | Traglia, Michela | Ulivi, Sheila | Westra, Harm-Jan | Yang, Jian | Zhao, Jing Hua | Anni, Franco | Abdellaoui, Abdel | Attwood, Antony | Balkau, Beverley | Bandinelli, Stefania | Bastardot, François | Benyamin, Beben | Boehm, Bernhard O. | Cookson, William O. | Das, Debashish | de Bakker, Paul I. W. | de Boer, Rudolf A. | de Geus, Eco J. C. | de Moor, Marleen H. | Dimitriou, Maria | Domingues, Francisco S. | Döring, Angela | Engström, Gunnar | Eyjolfsson, Gudmundur Ingi | Ferrucci, Luigi | Fischer, Krista | Galanello, Renzo | Garner, Stephen F. | Genser, Bernd | Gibson, Quince D. | Girotto, Giorgia | Gudbjartsson, Daniel Fannar | Harris, Sarah E. | Hartikainen, Anna-Liisa | Hastie, Claire E. | Hedblad, Bo | Illig, Thomas | Jolley, Jennifer | Kähönen, Mika | Kema, Ido P. | Kemp, John P. | Liang, Liming | Lloyd-Jones, Heather | Loos, Ruth J. F. | Meacham, Stuart | Medland, Sarah E. | Meisinger, Christa | Memari, Yasin | Mihailov, Evelin | Miller, Kathy | Moffatt, Miriam F. | Nauck, Matthias | Novatchkova, Maria | Nutile, Teresa | Olafsson, Isleifur | Onundarson, Pall T. | Parracciani, Debora | Penninx, Brenda W. | Perseu, Lucia | Piga, Antonio | Pistis, Giorgio | Pouta, Anneli | Puc, Ursula | Raitakari, Olli | Ring, Susan M. | Robino, Antonietta | Ruggiero, Daniela | Ruokonen, Aimo | Saint-Pierre, Aude | Sala, Cinzia | Salumets, Andres | Sambrook, Jennifer | Schepers, Hein | Schmidt, Carsten Oliver | Silljé, Herman H. W. | Sladek, Rob | Smit, Johannes H. | Starr, John M. | Stephens, Jonathan | Sulem, Patrick | Tanaka, Toshiko | Thorsteinsdottir, Unnur | Tragante, Vinicius | van Gilst, Wiek H. | van Pelt, L. Joost | van Veldhuisen, Dirk J. | Völker, Uwe | Whitfield, John B. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Wirnsberger, Gerald | Algra, Ale | Cucca, Francesco | d’Adamo, Adamo Pio | Danesh, John | Deary, Ian J. | Dominiczak, Anna F. | Elliott, Paul | Fortina, Paolo | Froguel, Philippe | Gasparini, Paolo | Greinacher, Andreas | Hazen, Stanley L. | Jarvelin, Marjo-Riitta | Khaw, Kay Tee | Lehtimäki, Terho | Maerz, Winfried | Martin, Nicholas G. | Metspalu, Andres | Mitchell, Braxton D. | Montgomery, Grant W. | Moore, Carmel | Navis, Gerjan | Pirastu, Mario | Pramstaller, Peter P. | Ramirez-Solis, Ramiro | Schadt, Eric | Scott, James | Shuldiner, Alan R. | Smith, George Davey | Smith, J. Gustav | Snieder, Harold | Sorice, Rossella | Spector, Tim D. | Stefansson, Kari | Stumvoll, Michael | Wilson Tang, W. H. | Toniolo, Daniela | Tönjes, Anke | Visscher, Peter M. | Vollenweider, Peter | Wareham, Nicholas J. | Wolffenbuttel, Bruce H. R. | Boomsma, Dorret I. | Beckmann, Jacques S. | Dedoussis, George V. | Deloukas, Panos | Ferreira, Manuel A. | Sanna, Serena | Uda, Manuela | Hicks, Andrew A. | Penninger, Josef Martin | Gieger, Christian | Kooner, Jaspal S. | Ouwehand, Willem H. | Soranzo, Nicole | Chambers, John C
Nature  2012;492(7429):369-375.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
doi:10.1038/nature11677
PMCID: PMC3623669  PMID: 23222517
The British journal of nutrition  2012;109(7):1196-1210.
Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno–fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS) genotypes modulate the amounts of LC-PUFA in maternal blood. Whether FADS genotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and child FADS genotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasma n-6 and n-3 fatty acids were analysed for association with seventeen FADS gene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and child FADS genotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursor n-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturated n-6 LC-PUFA. This first study on FADS genotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism.
doi:10.1017/S0007114512003108
PMCID: PMC3600399  PMID: 22877655
FADS; Fetal fatty acid supply; Cord blood; Avon Longitudinal Study of Parents and Children (ALSPAC)
Diabetes  2012;61(2):391-400.
Rapid postnatal growth is associated with increased risk of childhood adiposity. The aim of this study was to establish whether this pathway is mediated by altered DNA methylation and gene expression. Two distinct cohorts, one preterm (n = 121) and one term born (n = 6,990), were studied. Exploratory analyses were performed using microarrays to identify differentially expressed genes in whole blood from children defined as “slow” (n = 10) compared with “rapid” (n = 10) postnatal (term to 12 weeks corrected age) growers. Methylation within the identified TACSTD2 gene was measured in both cohorts, and rs61779296 genotype was determined by Pyrosequencing or imputation and analyzed in relation to body composition at 9–15 years of age. In cohort 1, TACSTD2 expression was inversely correlated with methylation (P = 0.016), and both measures were associated with fat mass (expression, P = 0.049; methylation, P = 0.037). Although associated with gene expression (cohort 1, P = 0.008) and methylation (cohort 1, P = 2.98 × 10−11; cohort 2, P = 3.43 × 10−15), rs61779296 was not associated with postnatal growth or fat mass in either cohort following multiple regression analysis. Hence, the lack of association between fat mass and a methylation proxy SNP suggests that reverse causation or confounding may explain the initial association between fat mass and gene regulation. Noncausal methylation patterns may still be useful predictors of later adiposity.
doi:10.2337/db11-1039
PMCID: PMC3266428  PMID: 22190649
PLoS ONE  2012;7(12):e51084.
Vitamin B-12 is essential for the development and maintenance of a healthy nervous system. Brain development occurs primarily in utero and early infancy, but the role of maternal vitamin B-12 status during pregnancy on offspring cognitive function is unclear. In this study we assessed the effect of vitamin B-12 status in well-nourished pregnant women on the cognitive ability of their offspring in a UK birth cohort (ALSPAC). We then examined the association of SNPs in maternal genes FUT2 (rs492602) and TCN2 (rs1801198, rs9606756) that are related to plasma vitamin B-12, with offspring IQ. Observationally, there was a positive association between maternal vitamin B-12 intake and child’s IQ that was markedly attenuated after adjustment for potential confounders (mean difference in offspring IQ score per doubling of maternal B-12 intake, before adjustment: 2.0 (95% CI 1.3, 2.8); after adjustment: 0.7 (95% CI −0.04, 1.4)). Maternal FUT2 was weakly associated with offspring IQ: mean difference in IQ per allele was 0.9 (95% CI 0.1, 1.6). The expected effect of maternal vitamin B-12 on offspring IQ, given the relationships between SNPs and vitamin B-12, and SNPs and IQ was consistent with the observational result. Our findings suggest that maternal vitamin B-12 may not have an important effect on offspring cognitive ability. However, further examination of this issue is warranted.
doi:10.1371/journal.pone.0051084
PMCID: PMC3515553  PMID: 23227234
Human mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
doi:10.1002/humu.21526
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
Human Mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population. Hum Mutat 32:1–11, 2011. © 2011 Wiley-Liss, Inc.
doi:10.1002/humu.21526
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
BMC Medical Genetics  2012;13:90.
Background
In observational epidemiological studies type 2 diabetes (T2D) and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding.
Methods
In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child’s intelligence quotient (IQ) scores in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We generated a fasting glucose (FGGRS) and a T2D (T2DGRS) genetic risk score and used them in a Mendelian randomization approach.
Results
We found a strong correlation between the FGGRS and fasting glucose plasma measurements that were available for a subset of children, but no association of either the maternal or the offspring FGGRS with child’s IQ was observed. In contrast, the maternal T2DGRS was positively associated with offspring IQ.
Conclusions
Maternal and offspring genetic variants which are associated with glucose levels are not associated with offspring IQ, suggesting that there is unlikely to be a causal link between glucose exposure in utero and IQ in childhood. Further exploration in even larger cohorts is required to exclude the possibility that our null findings were due to a lack of statistical power.
doi:10.1186/1471-2350-13-90
PMCID: PMC3570299  PMID: 23013243
Mendelian randomization; Fasting glucose; Type 2 diabetes; IQ; ALSPAC

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