The SLC6A14 gene shows evidence of association with obesity

Abstract

In our previous genome-wide scan of Finnish nuclear families, obesity was linked to chromosome Xq24. Here we analyzed this 15-Mb region by genotyping 9 microsatellite markers and 36 single nucleotide polymorphisms (SNPs) for 11 positional and functional candidate genes in an extended sample of 218 obese Finnish sibling pairs (sibpairs) (BMI > 30 kg/m2). Evidence of linkage emerged mainly from the obese male sibpairs, suggesting a gender-specific effect for the underlying gene. By constructing haplotypes among the obese male sibpairs, we restricted the region from 15 Mb to 4 Mb, between markers DXS8088 and DXS8067. Regional functional candidate genes were tested for association in an initial sample of 117 cases and 182 controls. Significant evidence was observed for association for an SNP in the 3'-untranslated region of the solute carrier family 6 member 14 (SLC6A14) gene (P = 0.0002) and for SNP haplotypes of the SLC6A14 gene (P = 0.0007-0.006). Furthermore, an independent replication study sample of 837 cases and 968 controls from Finland and Sweden also showed significant differences in allele frequencies between obese and non-obese individuals (P = 0.003). The SLC6A14 gene is an interesting novel candidate for obesity because it encodes an amino acid transporter, which potentially regulates tryptophan availability for serotonin synthesis and thus possibly affects appetite control.

Figure 1

(a) The genes and microsatellite markers on chromosome Xq22–26 selected for this study. Distances and order are based on the public NCBI and commercial Celera Genomics databases. (b) Structure of the SLC6A14 gene and locations of the genotyped SNPs. (c) SNPs, their locations in the SLC6A14 gene, and the surrounding sequence (SNP nucleotides are capitalized).

Figure 2

Haplotype sharing on Xq23–24 among male sibpairs within families and between families. The major haplotype of the SLC6A14 gene (303A-20649C-22510G) is shared by 16 families and the shared haplotype partially extends to the neighboring markers.