Genetically regulated gene expression underlies lipid traits in Hispanic cohorts

Abstract

Plasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted in genetic variation underlying lipid levels, they mainly comprise individuals of European ancestry and thus their transferability to non-European populations is unclear. We performed genome-wide (GWAS) and imputed transcriptome-wide association studies of four lipid traits in the Hispanic Community Health Study/Study of Latinos cohort (HCHS/SoL, n = 11,103), replicated top hits in the Multi-Ethnic Study of Atherosclerosis (MESA, n = 3,855), and compared the results to the larger, predominantly European ancestry meta-analysis by the Global Lipids Genetics Consortium (GLGC, n = 196,475). In our GWAS, we found significant SNP associations in regions within or near known lipid genes, but in our admixture mapping analysis, we did not find significant associations between local ancestry and lipid phenotypes. In the imputed transcriptome-wide association study in multiple tissues and in different ethnicities, we found 59 significant gene-tissue-phenotype associations (P < 3.61×10 −8 ) with 14 unique significant genes, many of which occurred across multiple phenotypes, tissues, and ethnicities and replicated in MESA (45/59) and in GLGC (44/59). These include well-studied lipid genes such as SORT1 , CETP , and PSRC1 , as well as genes that have been implicated in cardiovascular phenotypes, such as CCL22 and ICAM1 . The majority (40/59) of significant associations colocalized with expression quantitative trait loci (eQTLs), indicating a possible mechanism of gene regulation in lipid level variation. To fully characterize the genetic architecture of lipid traits in diverse populations, larger studies in non-European ancestry populations are needed.

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer’s dementia

“…These results showed that the genetic factor of gene ZNF234 on AD could be potentially mediated through its gene expression, and the expression of this gene could be also potentially involved in the mechanisms of both AD pathology indices of β -amyloid and tangles. Besides AD, gene ZNF234 is also a known risk gene for lipid traits [ 45 ]. The genetically regulated gene expression of this gene might also affect lipid traits, thus leading to a pleiotropy phenomenon of AD and lipid traits [ 46 ].…”

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer’s dementia

“…These results showed that the genetic factor of gene ZNF234 on AD could be potentially mediated through its gene expression, and the expression of this gene could be also potentially involved in the mechanisms of both AD pathology indices of β -amyloid and tangles. Besides AD, gene ZNF234 is also a known risk gene for lipid traits [43]. The genetically regulated gene expression of this gene might also affect lipid traits, thus leading to a pleiotropy phenomenon of AD and lipid traits [44].…”

“…is also a known risk gene for lipid traits [43]. The genetically regulated gene expression of this gene might also affect lipid traits, thus leading to a pleiotropy phenomenon of AD and lipid traits [44].…”

Transcriptome-wide Association Study of Blood Cell Traits in African Ancestry and Hispanic/Latino Populations

“…Transcripts whose levels can be confidently imputed from genetic variants are then assessed for phenotype associations [15]. However, like GWAS, TWAS analyses have often included only EA populations [16,17], though some recent efforts have included more diverse populations [18][19][20][21][22]. Furthermore, most reference eQTL datasets used for TWAS include predominantly EA American individuals [23,24], limiting the predictive power of this novel method in other populations with different allele frequencies.…”