[Show abstract][Hide abstract] ABSTRACT: A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index
are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex-
and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873
children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05
SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining
all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in
childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index
and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass
Full-text · Article · Nov 2015 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Eczema often precedes the development of asthma in a disease course called the a € atopic marcha €. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Full-text · Article · Nov 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N=28,459). We identified 7 independent top SNPs (P<1x10(-6)) for birth length, of which 3 were novel and 4 were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The 3 novel SNPs were followed-up in 9 replication studies (Stage 2; N=11,995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1+2; ß=0.046, S.E.=0.008, P=2.46x10(-8), explained variance=0.05%). Rs905938 was also associated with infant length (N=28,228; P=5.54x10(-4)) and adult height (N=127,513; P=1.45x10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
No preview · Article · Oct 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
[Show abstract][Hide abstract] ABSTRACT: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11,000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of MKL2 (P=8.9 x 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P=4.6 x 10(-5)) and short adult stature (P=1.1 x 10(-11)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes.Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, BMI-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes, and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
Full-text · Article · Apr 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Objective
Four putative single nucleotide polymorphism (SNP) risk variants at the preeclampsia susceptibility locus on chromosome 2q22; rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preeclampsia risk variants in an independent Australian population-based cohort.
The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1246 mothers and 1404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software.
Nominal associations (P < 0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P = 0.005) and decreased blood glucose levels in adolescents (P = 0.022). The LRP1B SNP was associated with increased maternal height (P = 0.026) and decreased maternal weight (P = 0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P = 0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preeclamptic pregnancy (P = 0.003) and having a mother with prior preeclamptic pregnancy (P = 0.033).
Our collective findings support the hypothesis that genetic mechanisms for preeclampsia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P < 0.001).
[Show abstract][Hide abstract] ABSTRACT: Rationale: Vitamin D deficiency is associated with chronic lung disease. We have previously shown in an in vivo mouse model that maternal vitamin D deficiency is associated with alterations in early life lung structure and function. However, there are limited data to support a relationship between maternal vitamin D deficiency during the early stages of lung development and post-natal lung function in human populations. Objectives: To assess the association between maternal vitamin D deficiency, post-natal lung function and asthmatic status in a longitudinal birth cohort. Methods: Serum was collected at 16-20 weeks gestation at the time of recruitment in a community based prospective birth cohort for measurement of vitamin D (25(OH)D). Lung function was assessed by spirometry according to ATS guidelines in children at 6 and 14 years of age. Demographic and clinical history data were collected by questionnaire at recruitment and at the follow up visits. Measurements and Main Results: FVC Z-scores in both sexes (β; 0.007[0.001, 0.013], p = 0.02) and FEV1 Z-scores in females (β; 0.007[0.001, 0.013], p = 0.02) were positively associated with maternal serum 25(OH)D at 6 years of age. These associations were mostly absent at 14 years of age. Maternal vitamin D deficiency was positively associated with asthma at 6 years of age but only in males (OR; 3.03(1.02-9.02), p = 0.04). Conclusions: This study supports the notion that vitamin D deficiency during lung development may impact on post-natal lung growth and increase the risk of developing lung disease.
No preview · Article · Mar 2014 · Annals of the American Thoracic Society
[Show abstract][Hide abstract] ABSTRACT: Abstract
To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.
We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.
We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).
At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10-9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10-8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10-7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10-6).
By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.
No preview · Article · Dec 2013 · Journal of Allergy and Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009 < P-replication <=0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.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).
Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
[Show abstract][Hide abstract] ABSTRACT: During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
[Show abstract][Hide abstract] ABSTRACT: Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replicate this finding and identify other genetic markers of corneal astigmatism in an Australian population of Northern European ancestry.
Data from two cohorts were included in this study. The first cohort consisted of 1,013 individuals who were part of the Western Australian Pregnancy Cohort (Raine) Study: 20-year follow-up Eye Study. The second cohort comprised 1,788 individuals of 857 twin families who were recruited through the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study. Corneal astigmatism was calculated as the absolute difference between the keratometry readings in two meridians, and genotype data were extracted from genome-wide arrays. Initially, each cohort was analyzed separately, before being combined for meta- and subsequent genome-wide pathway analysis.
Following meta-analysis, SNP rs7677751 at the PDGFRA locus had a combined p=0.32. No variant was found to be statistically significantly associated with corneal astigmatism at the genome-wide level (p<5.0×10(-8)). The SNP with strongest association was rs1164064 (p=1.86×10(-6)) on chromosome 3q13. Gene-based pathway analysis identified a significant association between the Gene Ontology "segmentation" (GO:0035282) pathway, corrected p=0.009.
Our data suggest that the PDGFRA locus does not transfer a major risk of corneal astigmatism in people of Northern European ancestry. Better-powered studies are required to validate the novel putative findings of our study.
[Show abstract][Hide abstract] ABSTRACT: The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. While little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty, and cancer progression, pointing to shared underlying mechanisms.To discover genetic loci influencing pubertal height and growth and place them in context of overall growth and maturation, we performed genome-wide association (GWA) meta-analyses in up to 18,737 European samples utilizing longitudinally collected height measurements. We found significant associations (P<1.67 x 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased BMI, reduced pubertal growth, and earlier puberty.While epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty, and childhood obesity, and provides new information to pinpoint processes linking these traits.
No preview · Article · Feb 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The Raine Eye Health Study (REHS) was conceived to determine the prevalence of and risk factors for eye disease in young adults, and to characterize ocular biometric parameters in a young adult cohort. This article summarizes the rationale and study design of REHS and outlines the baseline prevalence of ophthalmic disease in this population.
The Western Australian Pregnancy Cohort (Raine) Study originated as a randomized-controlled trial of 2900 women recruited from the state's largest maternity hospital. Their offspring (N = 2868) have been followed at birth, ages 1, 2, 3, 5, 8, 10, 14, 17 and 20 years of age in a prospective cohort study. DNA has been collected from participants for genome-wide association studies. At the 20-year follow-up participants completed a comprehensive eye assessment that included visual acuity, orthoptic assessment and cycloplegic autorefraction, as well as several ocular biometric variables and multiple ophthalmic photographs of the anterior and posterior segments.
A total of 1344 participants (51.3% male) were assessed over a 24-month period. For the majority of examined participants (85.5%) both parents were Caucasian, 63.3% had completed school year 12 or equivalent, 5.5% had myopia (spherical equivalent ≤-3 diopters) and 15 participants (1.2%) had unilateral or bilateral pterygia. Keratoconus, cataract, keratitis and uveitis were rare.
The REHS design and methodology allow comparison with other population-based studies of eye disease. The study established the prevalence of eye disorders in a large sample of predominantly Caucasian young Australian adults.
No preview · Article · Jan 2013 · Ophthalmic Genetics
[Show abstract][Hide abstract] ABSTRACT: A r t i c l e s Human ocular biometric parameters comprise a set of highly herit-able and often correlated quantitative traits. One notable example is CCT, which has an estimated heritability of up to 95% (ref. 1). Whereas extreme corneal thinning is a dramatic clinical feature for rare congenital connective tissue disorders, including brittle cornea syndrome (BCS) and several types of osteogenesis imperfecta 2,3 , mildly reduced CCT is involved in more common and late-onset eye diseases. It is a hallmark of keratoconus and a risk factor for primary open-angle glaucoma (POAG) in individuals with ocular hypertension 4,5 . Previous genome-wide association studies (GWAS) conducted on both European and Asian populations have identi-fied 11 CCT-associated loci 6–9 . Among these loci, mutations in ZNF469 (refs. 10–12), COL5A1 (ref. 13) and COL8A2 (refs. 14,15) are known to cause rare disorders of BCS, Ehlers-Danlos syndrome (EDS) and corneal dystrophy, respectively. However, none was found to be associated with common eye diseases. Keratoconus is a common corneal ectasia, affecting 1 in 2,000 in the general population 16 . It is a progressive eye disease character-ized by thinning and asymmetrical conical protrusion of the cornea, which causes variable and severe visual impairment. Owing to the limited availability of medical treatments, keratoconus is one of the leading causes of corneal transplantation worldwide 17 . Two GWAS have been conducted on susceptibility for keratoconus, and these studies suggested some new genetic associations, but neither study reported genome-wide significant loci 18,19 . POAG is the most com-mon form of glaucoma, which is the second leading cause of blind-ness worldwide 20 . Several risk loci for POAG have been identified through early linkage and candidate gene studies 21,22 and recent Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus
[Show abstract][Hide abstract] ABSTRACT: Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.