Open AccessIdentification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey
Author(s) -
Cassandra N. Spracklen,
Jianxin Shi,
Swarooparani Vadlamudi,
Ying Wu,
Meng Zou,
Chelsea K. Raulerson,
James P. Davis,
Monica Zeynalzadeh,
Kayla Jackson,
Wentao Yuan,
Haifeng Wang,
Weihua Shou,
Ying Wang,
Jingchun Luo,
Leslie A. Lange,
Ethan M. Lange,
Barry M. Popkin,
Penny GordonLarsen,
Shufa Du,
Wei Huang,
Karen L. Mohlke
Publication year - 2018
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1007275
Subject(s) - biology , expression quantitative trait loci , genome wide association study , genetics , quantitative trait locus , glucose homeostasis , locus (genetics) , population , allele , genetic association , single nucleotide polymorphism , endocrinology , insulin , gene , genotype , insulin resistance , medicine , environmental health
To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2 , we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3 , SIX2 , and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2 , we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus.