A Robust Method for Genome‐Wide Association Meta‐Analysis With the Application to Circulating Insulin‐Like Growth Factor I Concentrations

Genome‐wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta‐analysis is a cost‐efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene‐gene and gene‐environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta‐analysis methods, rendering such analyses less optimal for the detecting association. This article describes a test that improves meta‐analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating insulin‐like growth factor I concentrations.     

Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function

Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the β-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ～3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function.     

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10^–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10^–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

     

CUBN is a gene locus for albuminuria

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.     

A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.