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1.  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
2.  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
4.  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
5.  Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill 
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
6.  Coordinated Genetic Scaling of the Human Eye: Shared Determination of Axial Eye Length and Corneal Curvature 
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
7.  Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC) 
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)
8.  Postnatal Growth and DNA Methylation Are Associated With Differential Gene Expression of the TACSTD2 Gene and Childhood Fat Mass 
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
9.  ACTN3 genotype, athletic status and lifecourse physical capability: meta-analysis of the published literature and findings from nine studies 
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
10.  ACTN3 Genotype, Athletic Status, and Life Course Physical Capability: Meta-Analysis of the Published Literature and Findings from Nine Studies 
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
11.  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
12.  DNA Methylation Patterns in Cord Blood DNA and Body Size in Childhood 
PLoS ONE  2012;7(3):e31821.
Background
Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood.
Principal Findings
A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean ± standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m2. This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>1.2-fold and p<10−4) were analysed to determine DNA methylation levels at 1–3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing (ALPL with height, pCorrected = 0.017).
Conclusions
DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality.
doi:10.1371/journal.pone.0031821
PMCID: PMC3303769  PMID: 22431966
13.  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
14.  Adult height variants affect birth length and growth rate in children 
Human Molecular Genetics  2011;20(20):4069-4075.
Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ∼10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth. A total of 7768 participants in the Avon Longitudinal Study of Parents and Children had data available. Individual growth trajectories from 0 to 10 years were estimated using mixed-effects linear spline models and differences in trajectories by individual SNPs and allelic score were determined. The allelic score was associated with birth length (0.026 cm increase per ‘tall’ allele, SE = 0.003, P = 1 × 10−15, equivalent to 0.017 SD). There was little evidence of association between the allelic score and early infancy growth (0–3 months), but there was evidence of association between the allelic score and later growth. This association became stronger with each consecutive growth period, per ‘tall’ allele per month effects were 0.015 SD (3 months–1 year, SE = 0.004), 0.023 SD (1–3 years, SE = 0.003) and 0.028 SD (3–10 years, SE = 0.003). By age 10, the mean height difference between individuals with ≤170 versus ≥191 ‘tall’ alleles (the top and bottom 10%) was 4.7 cm (0.8 SD), explaining ∼5% of the variance. There was evidence of associations with specific growth periods for some SNPs (rs3791675, EFEMP1 and rs6569648, L3MBTL3) and supportive evidence for previously reported age-dependent effects of HHIP and SOCS2 SNPs. SNPs associated with adult height influence birth length and have an increasing effect on growth from late infancy through to late childhood. By age 10, they explain half the height variance (∼5%) of that explained in adults (∼10%).
doi:10.1093/hmg/ddr309
PMCID: PMC3177650  PMID: 21757498
15.  Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index 
Background Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers.
Methods We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24 198) and then tested for a genotype × smoking status interaction.
Results There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m2 [95% confidence interval (95% CI): −0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m2 (95% CI: 0.13–0.31) lower BMI (P = 8 × 10−6). The effect size was larger in current [0.33 kg/m2 lower BMI per T-allele (95% CI: 0.18–0.48); P = 6 × 10−5], than in former smokers [0.16 kg/m2 (95% CI: 0.03–0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001).
Conclusions Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI.
doi:10.1093/ije/dyr077
PMCID: PMC3235017  PMID: 21593077
Smoking; BMI; SNP; genetic association; interaction
16.  Association Between a High-Risk Autism Locus on 5p14 and Social Communication Spectrum Phenotypes in the General Population 
The American journal of psychiatry  2010;167(11):1364-1372.
Objective
Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.
Method
Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout.
Results
Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple subthreshold social, communicative, and cognitive impairments.
Conclusions
Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.
doi:10.1176/appi.ajp.2010.09121789
PMCID: PMC3008767  PMID: 20634369
17.  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
18.  Association of COMT Val108/158Met Genotype and Cigarette Smoking in Pregnant Women 
Nicotine & Tobacco Research  2010;13(2):55-63.
Introduction:
Smoking behaviors, including heaviness of smoking and smoking cessation, are known to be under a degree of genetic influence. The enzyme catechol O-methyltransferase (COMT) is of relevance in studies of smoking behavior and smoking cessation due to its presence in dopaminergic brain regions. While the COMT gene is therefore one of the more promising candidate genes for smoking behavior, some inconsistencies have begun to emerge.
Methods:
We explored whether the rs4680 A (Met) allele of the COMT gene predicts increased heaviness of smoking and reduced likelihood of smoking cessation in a large population-based cohort of pregnant women. We further conducted a meta-analysis of published data from community samples investigating the association of this polymorphism with heaviness of smoking and smoking status.
Results:
In our primary sample, the A (Met) allele was associated with increased heaviness of smoking before pregnancy but not with the odds of continuing to smoke in pregnancy either in the first trimester or in the third trimester. Meta-analysis also indicated modest evidence of association of the A (Met) allele with increased heaviness of smoking but not with persistent smoking.
Conclusions:
Our data suggest a weak association between COMT genotype and heaviness of smoking, which is supported by our meta-analysis. However, it should be noted that the strength of evidence for this association was modest. Neither our primary data nor our meta-analysis support an association between COMT genotype and smoking cessation. Therefore, COMT remains a plausible candidate gene for smoking behavior phenotypes, in particular, heaviness of smoking.
doi:10.1093/ntr/ntq209
PMCID: PMC3028189  PMID: 21106664
19.  PCSK6 is associated with handedness in individuals with dyslexia 
Human Molecular Genetics  2010;20(3):608-614.
Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)]. The most highly associated marker, rs11855415 (P = 4.7 × 10−7), is located within PCSK6. Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill. Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 2.0 × 10−8). Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 0.0020). These results provide molecular evidence that cerebral asymmetry and dyslexia are linked. Furthermore, PCSK6 is a protease that cleaves the left–right axis determining protein NODAL. Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia.
doi:10.1093/hmg/ddq475
PMCID: PMC3016905  PMID: 21051773
20.  Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth 
Diabetes  2009;58(6):1428-1433.
OBJECTIVE
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
RESEARCH DESIGN AND METHODS
We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
RESULTS
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.
CONCLUSIONS
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
doi:10.2337/db08-1739
PMCID: PMC2682672  PMID: 19228808
21.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
22.  Type 2 Diabetes Risk Alleles are Associated with Reduced Size at Birth 
Diabetes  2009;58(6):1428-1433.
Objective
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
Research design and methods
We genotyped single nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2 and SLC30A8) in 7986 mothers and 19200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
Results
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus: 21g [95%CI:11-31g], P=2×10-5 and 14g [4-23g], P=0.004 lower birth weight per risk allele, respectively. The 4% of offspring carrying four risk alleles at these two loci were 80g [39-120g] lighter at birth than the 8% carrying none (Ptrend =5×10-7). There were no associations between birth weight and fetal genotypes at the three other loci, or maternal genotypes at any locus.
Conclusions
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
doi:10.2337/db08-1739
PMCID: PMC2682672  PMID: 19228808
23.  A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women 
Human Molecular Genetics  2009;18(22):4457-4466.
Pregnant women are advised to abstain from alcohol despite insufficient evidence on the fetal consequences of moderate prenatal alcohol use. Mendelian randomization could help distinguish causal effects from artifacts due to residual confounding and measurement errors; however, polymorphisms reliably associated with alcohol phenotypes are needed. We aimed to test whether alcohol dehydrogenase (ADH) gene variants were associated with alcohol use before and during pregnancy. Ten variants in four ADH genes were genotyped in women from South-West England. Phenotypes of interest were quantity and patterns of alcohol consumption before and during pregnancy, including quitting alcohol following pregnancy recognition. We tested single-locus associations between genotypes and phenotypes with regression models. We used Bayesian models (multi-locus) to take account of linkage disequilibrium and reanalyzed the data with further exclusions following two conservative definitions of ‘white ethnicity’ based on the woman's reported parental ethnicity or a set of ancestry-informative genetic markers. Single-locus analyses on 7410 women of white/European background showed strong associations for rs1229984 (ADH1B). Rare allele carriers consumed less alcohol before pregnancy [odds ratio (OR) = 0.69; 95% confidence interval (CI): 0.56–0.86, P = 0.001], were less likely to have ‘binged’ during pregnancy (OR = 0.55, 95% CI: 0.38–0.78, P = 0.0009), and more likely to have abstained in the first trimester of gestation (adjusted OR = 1.42, 95% CI: 1.12–1.80, P = 0.004). Multi-locus models confirmed these results. Sensitivity analyses did not suggest the presence of residual population stratification. We confirmed the established association of rs1229984 with reduced alcohol consumption over the life-course, contributing new evidence of an effect before and during pregnancy.
doi:10.1093/hmg/ddp388
PMCID: PMC2766294  PMID: 19687126
24.  A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy 
Human Molecular Genetics  2009;18(15):2922-2927.
Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes. Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some pregnant women continue to smoke. A recent genome-wide association study demonstrated an association between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy, we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds (95% CI 1.11–1.45) of continued smoking during pregnancy (P = 0.0006). Adjustment for pre-pregnancy smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03–1.39); P = 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the first, but not the last, trimester [OR for smoking 10+ cigarettes/day versus 1–9/day in first trimester = 1.30 (95% CI 1.13–1.50); P = 0.0003]. To conclude, we have found strong evidence of association between the rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the previously observed association with smoking quantity. Our data support the role of genetic factors in influencing smoking cessation during pregnancy.
doi:10.1093/hmg/ddp216
PMCID: PMC2706684  PMID: 19429911
25.  Ghrelin receptor gene polymorphisms and body size in children and adults 
Background
The growth hormone secretagogue receptor type 1a gene (GHSR) encodes the cognate receptor of ghrelin, a gut hormone that regulates food intake and pituitary growth hormone secretion. Previous studies in US families and in a German population suggested GHSR to be a candidate quantitative locus for association with human obesity and growth.
Aim
To test common genetic variation in GHSR for association with body size in children and adults.
Methods
Sequencing was performed to systematically identify novel single nucleotide polymorphisms (SNPs) in GHSR. A set of three haplotype-tagging (ht)SNPs was identified which captured all the genetic variation in GHSR. These three htSNPs were then genotyped in three large population-based UK cohort studies (two adult and one childhood cohort) comprising 5,807 adults and 843 children.
Results
No significant genotype or haplotype associations were found with adult or childhood height, weight or BMI.
Conclusion
Common variation in GHSR is not associated with body size in UK adults or children.
doi:10.1210/jc.2008-0366
PMCID: PMC2579991  PMID: 18647811
ghrelin; ghrelin receptor; body mass index; gene; growth; ALSPAC; Ely Study

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