The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians

Abstract

Metabolic traits are heritable phenotypes widely-used in assessing the risk of various diseases. We conduct a genome-wide association analysis (GWAS) of nine metabolic traits (including glycemic, lipid, liver enzyme levels) in 125,872 Korean subjects genotyped with the Korea Biobank Array. Following meta-analysis with GWAS from Biobank Japan identify 144 novel signals (MAF ≥ 1%), of which 57.0% are replicated in UK Biobank. Additionally, we discover 66 rare (MAF < 1%) variants, 94.4% of them co-incident to common loci, adding to allelic series. Although rare variants have limited contribution to overall trait variance, these lead, in carriers, substantial loss of predictive accuracy from polygenic predictions of disease risk from common variant alone. We capture groups with up to 16-fold variation in type 2 diabetes (T2D) prevalence by integration of genetic risk scores of fasting plasma glucose and T2D and the I349F rare protective variant. This study highlights the need to consider the joint contribution of both common and rare variants on inherited risk of metabolic traits and related diseases.

Whole-genome sequencing of half-a-million UK Biobank participants

“…We found rs7412-T is significantly associated with lower Apolipoprotein B (apoB), Lipoprotein A, LDL, total cholesterol, and lower risk of lipoprotein metabolism disorder (ICD10: E78) across ancestries with concordant effects. This is consistent with published evidence of rs7412-T association with lipid biomarkers in Europeans, Africans, Asians, and Hispanics [28][29][30][31][32][33][34][35][36] ; lower apoB has been linked to reduced AD risk, with causality to be confirmed 32,[37][38][39][40][41][42][43] . As expected, rs429358-C, is associated with higher risk of dementia and cognitive disorders (F01-F09), intracranial hemorrhage and cerebrovascular disease (ICD10: I60-I69).…”

Genetic associations between circulating metabolic biomarkers and lung cancer in East Asians and Europeans

“…In this study, we included six circulating metabolic biomarkers, including high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), triglyceride (TG), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c), as the exposures. The GWAS summary data of the six biomarkers of East Asians were retrieved from Korea Biobank Array Project [ 20 ], in which 125,872 Koreans were involved and 8.3 million variants were genotyped and imputed (Table 1 ). For Europeans, the GWAS of blood lipid traits and glucose traits were retrieved from the Global Lipids Genetics Consortium (GLGC) [ 21 ] and the MAGIC (the Meta-Analyses of Glucose and Insulin-related traits Consortium) [ 22 , 23 ], respectively (Table 1 ).…”

“…In this study, we only retrieved the GWAS summary data of European people. The details of quality control and statistical analysis of the exposure to GWAS have been shown in previous studies [ 20 – 23 ].…”

The Metabolic Role of MAP3K15: Genetic and Phenotypic Insights from the 23andMe Research Database and Genetics-Driven Recruitment

“…While rare variants, such as LoFs, can have large effects on complex traits, they typically only explain a small amount of population variance 15,16,17 . On the other hand, common variants tend to have small effect sizes individually on a given phenotype, yet in aggregate explain a large proportion of the observed heritability.…”