GWAS loci in or near ABC genes
Genome-wide association studies (GWAS) entail the genotyping of large numbers of single nucleotide polymorphisms (SNP) and individuals with (cases) and without (controls) for a specific genetic disease or phenotype. By applying conservative statistical correction and replication in additional datasets, many loci in the human genome are associated with a wide range of conditions. Most GWAS loci are in non-coding regions of the genome and often affect the expression of nearby genes (Visscher et al., 2017). To identify common variants in or near ABC genes that may provide insight into their function, we searched the GWAS catalog, as well as the publicly available data from the UK Biobank study (Table 3 ).
There are several GWAS loci associated with levels of known substrates of ABC transporter genes. The ABCA1 gene is the cause of the recessive Tangier disease, a disorder of cholesterol transport to ApoA1 molecules. An SNP in an intron of ABCA1 , rs1883025, is highly associated (<10-50) in multiple studies with HDL and total cholesterol levels and to a lesser extent with triglyceride levels and metabolic syndrome (Spracklen et al., 2017; Willer et al., 2013). However, neither this SNP nor the closely linked rs2575876 are eQTLs for ABCA1 , and both have low regulomeDB scores, so the specific mechanism of action of this locus is unclear. Several studies link the ABCB4 gene (a bile acid transporter) to gallstone disease and gallbladder cancer, as well as cholesterol levels (Ferkingstad et al., 2018; Mhatre et al., 2017). The lead SNP for the gallstone association of ABCB4 , rs4148808, is in a large LD block in the gene’s promoter, with multiple predicted protein binding sites. Several GWAS studies for gout and uric acid levels identified associations in the ABCG2 gene in diverse populations (Dehghan et al., 2008; Woodward et al., 2009). The association peaks are inside theABCG2 gene and contain common functional missense and stop-codon variants (Q141K, Q126X) in the gene (Ichida, 2009; Matsuo et al., 2009; Woodward et al., 2009). The ABCG5 and ABCG8 genes are closely linked in a head-to-head arrangement. The rs6756629 SNP in anABCG8 intron is associated with cholesterol levels and gallstone disease. This SNP is in a block of polymorphisms that includes variants with high regulomeDB scores for adipose tissues.
Several additional GWAS loci near ABC genes involve plausible substrates. For example, the rs2062541 SNP in the ABCC1 gene is associated with blood carnitine levels (Shin et al., 2014) and N-acetylcarnosine levels. Response to the irinotecan chemotherapy drug is associated with loci near ABCC4 (Han et al., 2014). A locus in the ABCA6 gene is associated with LDL cholesterol levels and a locus in ABCA8 with HDL cholesterol (Surakka et al., 2015; Willer et al., 2013). Therefore, several phenotypes associated with variants in and near multiple ABC genes could be the basis for further functional follow-up studies.