Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error : the CREAM consortium

Peer reviewe

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia : The CREAM Consortium

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).Peer reviewe

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP x education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P <8.5 x 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.Peer reviewe

Candidate genes for FECD and related diseases of the cornea.

<p>The columns FECD and CCT indicate whether genes have been implicated in Fuchs dystrophy and central corneal thickness, respectively. The effects on CCT are those for rare (variant) alleles; “Increased” and “Decreased” indicate that the variant (minor) allele is associated with an increase or decrease in CCT. A-R syndrome, Axenfeld-Rieger syndrome; PPCD, posterior polymorphous corneal dystrophy; POAG, primary open angle glaucoma; CHED, congenital hereditary endothelial dystrophy; CDPD, corneal dystrophy and perceptive deafness (Harboyan syndrome).</p

Summary of genotyped samples.

<p>Unless otherwise indicated, statistics are shown as mean ± SD.</p>a<p>Total includes 87 individuals with FECD grade of 1–3 in worse eye, not classified as FECD cases or controls.</p>b<p>Average of two eyes, when available.</p

Nominally significant results from association analyses for CCT.

<p>Genes <i>FOXO1, AKAP6</i> and <i>AKAP13</i> showed no significant associations, and therefore do not appear in this table. Position, physical map position (NCBI human genome build 36); Ref. All., reference (minor) allele; effect, expected µm change in CCT per copy of the reference allele (additive model) or for presence of minor allele (dominant model). <i>p</i> values in <i>italics</i> are less than 0.05; in <b>bold,</b> less than 0.001 (the Bonferroni threshold for study-wide significance at the 0.05 level). *, dominant model.</p

Association analyses for FECD case/control status.

<p>Chr., chromosome; No. SNPs, number of SNPs in or near gene passing QC; Best SNP, SNP with smallest <i>p</i> value; Position, physical map position (NCBI human genome build 36); Ref. All., reference (minor) allele; OR, odds ratio per copy of the reference allele (additive model) or for presence of minor allele (dominant model). <i>p</i> values in <i>italics</i> are less than 0.05; in <b>bold,</b> less than 0.001. *, dominant model.</p