P5724Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia in Japanese
Authors: Kato K , Oguri M , Horibe H , Fujimaki T , Sakuma J , Takeuchi I , Murohara T , Yasukochi Y , Yamada Y 
Published: October 2019

Abstract

Background
The circulating concentrations of triglycerides, high density lipoprotein (HDL)–cholesterol, and low density lipoprotein (LDL)–cholesterol have a substantial genetic component, and the heritability of early-onset dyslipidemia is expected to be higher than that of late-onset forms of this condition.

Purpose
To identify genetic variants that confer susceptibility to early-onset hypertriglyceridemia, hypo–HDL-cholesterolemia, and hyper–LDL-cholesterolemia in Japanese. We have now performed exome-wide association studies (EWASs) for early-onset forms of these conditions.

Methods
A total of 8073 individuals aged ≤65 years was enrolled in the study. The EWASs for hypertriglyceridemia (2664 cases, 5294 controls), hypo–HDL-cholesterolemia (974 cases, 7085 controls), and hyper–LDL-cholesterolemia (2911 cases, 5111 controls) were performed with Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip arrays. The relation of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) that passed quality control to hypertriglyceridemia, hypo–HDL-cholesterolemia, or hyper–LDL-cholesterolemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, we applied Bonferroni's correction for statistical significance of association.

Results
The EWASs of allele frequencies revealed that 25, 28, or 65 SNPs were significantly associated with hypertriglyceridemia (P<1.60 × 10–6), hypo–HDL-cholesterolemia (P<1.61 × 10–6), or hyper–LDL-cholesterolemia (P<1.60 × 10–6), respectively. Multivariable logistic regression analysis with adjustment for age and sex showed that all 25, 28, or 65 of these SNPs were significantly related to hypertriglyceridemia (P<0.0005), hypo–HDL-cholesterolemia (P<0.0004), or hyper–LDL-cholesterolemia (P<0.0002), respectively. After examination of the relation of the identified SNPs to serum concentrations of triglycerides, HDL-cholesterol, or LDL-cholesterol, linkage disequilibrium of the SNPs, and results of previous genome-wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C-TMOD4, LPGAT1, EHD3, COL6A3, ZNF860-CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo–HDL-cholesterolemia, and three loci (KIAA0319-FAM65B, UBD, LOC105375015) for hyper–LDL-cholesterolemia. Network analysis showed that the 10 or three genes associated with hypo-HDL-cholesterolemia or hyper-LDL-cholesterolemia, respectively, had direct or indirect interactions with the 50 genes previously shown to be associated with dyslipidemia.

Conclusion
We have thus identified 12 novel loci that confer susceptibility to early-onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for hypertriglyceridemia, hypo–HDL-cholesterolemia, or hyper–LDL-cholesterolemia in Japanese.