Gene-based association study for lipid traits in diverse cohorts implicates [i]BACE1[i] and [i]SIDT2[i] regulation in triglyceride levels

13 Plasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted on lipid genetics, they mainly focus on Europeans and thus their transferability to diverse populations is unclear. We performed SNPand gene-level genome-wide association studies (GWAS) of four lipid traits in cohorts from Nigeria and the Philippines and compared them to the results of larger, predominantly European meta-analyses. Two previously implicated loci met genome-wide significance in our SNP-level GWAS in the Nigerian cohort, rs34065661 in CETP associated with HDL cholesterol (P = 9.0× 10−10) and rs1065853 upstream of APOE associated with LDL cholesterol (P = 6.6×10−9). The top SNP in the Filipino cohort associated with triglyceride levels (rs662799, P = 2.7×10−16) and has been previously implicated in other East Asian studies. While this SNP is located directly upstream of well known APOA5, we show it may also be involved in the regulation of BACE1 and SIDT2. Our gene-based association analysis, PrediXcan, revealed decreased expression of BACE1 and decreased expression of SIDT2 in several tissues, all driven by rs662799, significantly associate with increased triglyceride levels in Filipinos (FDR < 0.1). In addition, our PrediXcan analysis implicated gene regulation as the mechanism underlying the associations of many other previously discovered lipid loci. Our novel BACE1 and SIDT2 findings were confirmed using summary statistics from the Global Lipids Genetic Consortium (GLGC) meta-GWAS. 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 INTRODUCTION 31 Though 99.9% of the genome between humans is identical, millions of variant sites exist in 32 different frequencies between populations, which leads to differences in gene expression and other 33 complex traits (Brown et al., 2016). Since most GWAS have been conducted in European cohorts 34 and most databases are built upon European data, the results may not accurately extrapolate to 35 other global populations, which could lead to disparity within medicine (Bustamante et al., 2011). 36 This discrepancy is alarming considering urgent health issues worldwide, such as obesity and 37 cardiovascular disease. Lipid levels as a complex trait are increasingly concerning due to the 38 growing global rate of obesity caused by the increasing availability of high-fat foods and rapid 39 urbanization (Ellulu et al., 2014). Decreased high density lipoprotein (HDL) cholesterol levels and 40 increased low density lipoprotein (LDL) cholesterol and triglyceride (TRIG) levels are associated 41 with cardiovascular disease, the leading cause of death in the United States (Go et al., 2013). 42 Studies such as the Global Lipids Genetic Consortium (GLGC) acquire information predominantly 43 from Europeans, but lack information from other populations (Coram et al., 2015; Willer et al., 44 2013). We aim to help remedy this issue by studying lipid traits in diverse populations. We chose 45 two populations with lipid phenotypes available to study from the database of Genotypes and 46 Phenotypes: Yoruba in Ibadan, Nigeria, (Yoruba) and Filipino in Cebu, Philippines (Cebu) (Adair 47 et al., 2011; Wu et al., 2013). 48 At the time of our study, one of the largest available cholesterol SNP meta-analyses is the GLGC 49 (Willer et al., 2013). The cohort in that study consists of 188,577 European-ancestry individuals 50 and 7,898 non-European-ancestry individuals. 157 loci were found to be significantly associated 51 with total cholesterol (CHOL), HDL, TRIG, or LDL levels, and they conducted further gene set 52 enrichment analysis with MAGENTA (Ayellet et al., 2010). However, gene-level association studies 53 that integrate transcriptome data, like PrediXcan and TWAS, were not performed (Gamazon et al., 54 PeerJ reviewing PDF | (2017:10:20975:1:1:NEW 22 Dec 2017) Manuscript to be reviewed