Worldwide Population Variation and Haplotype Analysis at the Serotonin Transporter Gene SLC6A4 and Implications for Association Studies

Variation at the serotonin transporter gene, SLC6A4, has been associated with a variety of neuropsychiatric disorders and could be involved in other health-related phenotypes. To determine the extent of variation at SLC6A4, we genotyped 23 markers on approximately 2500 individuals from 47 global populations, including the promoter variable number tandem repeat (VNTR) and 2 single nucleotide polymorphisms (SNPs) immediately flanking its variable region (rs25531 and rs25532), the intron 2 VNTR, and 19 additional SNPs. We observed several rare alleles at the promoter VNTR (some novel) and population-specific distributions of the reported functional SNPs rs25531, rs25532, and rs6355, as well as two alleles at the intron 2 VNTR. Alleles of interest at the VNTRs occurred on specific haplotype backgrounds. The repeat-number variants at the promoter VNTR and the intron 2 VNTR, as well as the putative functional SNPs, showed ethnic variation in frequencies. The more common alleles at the VNTR polymorphisms show wide geographic distributions, whereas rare alleles at both show more restricted distributions. The derived alleles at the two functional SNPs in the promoter VNTR show restricted distributions and occur primarily on different repeat number alleles. Our findings illustrate significant variation worldwide at SLC6A4 and that the functionally implicated alleles at the SNPs rs25531, rs25532, and rs6355 occur on limited haplotypes and vary significantly in global distribution. Association studies at SLC6A4 cannot a priori extrapolate across populations and should account for the multiple polymorphisms with possible functional variation across this locus, rather than focusing solely on one or two polymorphisms as commonly seen.