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. 2018 Jan 29:6:e4314.
doi: 10.7717/peerj.4314. eCollection 2018.

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

Angela Andaleon  1   2 , Lauren S Mogil  1 , Heather E Wheeler  1   2   3   4
Affiliations

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

Angela Andaleon et al. PeerJ. .

Abstract

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 SNP- and 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.

Keywords: GWAS; Gene expression; Lipids; Population genetics; PrediXcan.

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Conflict of interest statement

The authors declare there are no competing interests.

Figures

Figure 1
Figure 1. LocusZoom plots of the most significant SNPs in (A) HDL (rs34065661) and (B) LDL (rs1065853) in Yoruba.
The color of each dot represents the SNP’s linkage disequilibrium r2 with the labeled SNP in the 1000 Genomes African populations.
Figure 2
Figure 2. The top Cebu GWAS signal, rs662799, which associated with TRIG levels is 571 bp upstream of APOA5.
The color of each dot represents the SNP’s linkage disequilibrium r2 with rs662799 in the 1000 Genomes East Asian populations.
Figure 3
Figure 3. Allele frequencies of TRIG associated SNP and driver of predicted expression models in multiple genes, rs662799, in 1000 Genome populations.
Figure generated with the Geography of Genetic Variants Browser (Marcus & Novembre, 2016).
Figure 4
Figure 4. PrediXcan results for the Cebu TRIG phenotype using gene expression models built in 44 GTEx tissues.
(A) Manhattan plot: −log10 P-values are plotted against the respective chromosomal position of each gene across all tissues. (B) QQ plot of observed versus expected −log10 P-values for each gene across all tissues.
Figure 5
Figure 5. TRIG levels vs. predicted expression of two genes in Cebu.
(A) BACE1 predicted expression using the GTEx ESPMCS prediction model. (B) SIDT2 predicted expression using the GTEx LCL prediction model.
Figure 6
Figure 6. PrediXcan results of genes with rs662799 or linked SNPs (r2 > 0.6) in their predictive models across tissues.
The size of the circle is proportional to the absolute value of the t-statistic in the PrediXcan association test and the color indicates the direction of effect (sign of the t-statistic, −1 or 1) multiplied by the prediction performance of the model (R2) for each gene-tissue combination. Only genes t>3 are plotted for clarity.
See this image and copyright information in PMC

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