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A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness.

ABSTRACT: Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.

SUBMITTER: Choquet H

PROVIDER: S-EPMC7289804 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness.

Choquet Hélène H Melles Ronald B RB Yin Jie J Hoffmann Thomas J TJ Thai Khanh K KK Kvale Mark N MN Banda Yambazi Y Hardcastle Alison J AJ Tuft Stephen J SJ Glymour M Maria MM Schaefer Catherine C Risch Neil N Nair K Saidas KS Hysi Pirro G PG Jorgenson Eric E

Communications biology 20200611 1

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly ass ...[more]

PMID: 32528159

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Project description:ImportanceThicker or thinner central corneas may lead to either overestimation or underestimation of intraocular pressure, which is the most important causal and treatable risk factor for glaucoma. However, the findings on the associations between diabetes, random glucose, and glycated hemoglobin A1c (HbA1c) with central corneal thickness (CCT) are conflicting.ObjectiveTo evaluate the associations between diabetes, random glucose, and HbA1c with CCT in a multiethnic Asian population.Design, setting, and participantsCross-sectional analysis of the Singapore Epidemiology of Eye Diseases (SEED) Study conducted from 2004 to 2011. A total of 10?033 Chinese, Malay, and Indian individuals 40 years or older residing in Singapore were recruited. Participants with incomplete information on diabetes status (448 participants), prior refractive or cataract surgery (1940 eyes), and corneal edema or dystrophy (29 eyes) were excluded. A meta-analysis was conducted to estimate the overall association of diabetes with CCT.ExposuresStandardized clinical examinations and interviewer-administered questionnaire to collect information about demographic, systemic, and ocular factors.Main outcomes and measuresMeasurement of CCT using ultrasound pachymetry.ResultsA total of 8846 adults (mean [SD] age, 57.9 [9.9] years; 4447 women [50.3%]) (17?201 eyes) were included in the final analyses. The CCT profile was similar among participants with and without diabetes (mean [SD] CCT, 545.3 [33.7] ?m vs 544.8 [33.9] ?m; P?=?.39). Following adjustments of age, sex, ethnicity, corneal curvature, axial length, and body mass index, CCT was a mean (SD) of 4.9 (0.8) ?m (95% CI, 3.3-6.5 ?m) thicker in patients with diabetes than those without diabetes. Multivariable analyses also showed that thicker CCT was associated with higher random glucose (per 10 mg/dL [to convert to mmol/L, multiply by 0.0555], ??=?0.3; 95% CI, 0.2-0.4) and higher HbA1c (per percentage, ??=?1.5; 95% CI, 1.0-2.1) (all P?<?.001). These associations were significant in the subgroup with diabetes but not in the subgroup without diabetes. A meta-analysis including 12 previous population- and clinical-based studies showed that CCT was 12.8 ?m (95% CI, 8.2-17.5 ?m) thicker in eyes of patients with diabetes.Conclusions and relevanceThese findings suggest that diabetes and hyperglycemia were associated with thicker CCT. This study provides useful information on the interpretation of intraocular pressure in patients with diabetes.

Project description:Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

Dataset Information

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness.

Publications

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness.

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