BackgroundThe organic cation transporter OCT1 (SLC22A1) mediates the uptake of vitamin B1, cationic drugs, and xenobiotics into hepatocytes. Nine percent of Caucasians lack or have very low OCT1 activity due to loss-of-function polymorphisms in OCT1 gene. Here we analyzed the global genetic variability in OCT1 to estimate the therapeutic relevance of OCT1 polymorphisms in populations beyond Caucasians and to identify evolutionary patterns of the common loss of OCT1 activity in humans.MethodsWe applied massively parallel sequencing to screen for coding polymorphisms in 1,079 unrelated individuals from 53 populations worldwide. The obtained data was combined with the existing 1000 Genomes data comprising an additional 1,092 individuals from 14 populations. The identified OCT1 variants were characterized in vitro regarding their cellular localization and their ability to transport 10 known OCT1 substrates. Both the population genetics data and transport data were used in tandem to generate a world map of loss of OCT1 activity.ResultsWe identified 16 amino acid substitutions potentially causing loss of OCT1 function and analyzed them together with five amino acid substitutions that were not expected to affect OCT1 function. The variants constituted 16 major alleles and 14 sub-alleles. Six major alleles showed improper subcellular localization leading to substrate-wide loss in activity. Five major alleles showed correct subcellular localization, but substrate-specific loss of activity. Striking differences were observed in the frequency of loss of OCT1 activity worldwide. While most East Asian and Oceanian individuals had completely functional OCT1, 80 % of native South American Indians lacked functional OCT1 alleles. In East Asia and Oceania the average nucleotide diversity of the loss-of-function variants was much lower than that of the variants that do not affect OCT1 function (ratio of 0.03) and was significantly lower than the theoretically expected heterozygosity (Tajima’s D = −1.64, P < 0.01).ConclusionsComprehensive genetic analyses showed strong global variations in the frequency of loss of OCT1 activity with selection pressure for maintaining OCT1 activity in East Asia and Oceania. These results not only enable pharmacogenetically-based optimization of drug treatment worldwide, but may help elucidate the functional role of human OCT1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0172-0) contains supplementary material, which is available to authorized users.

Gallstone disease is a common complex disease that confers a substantial economic burden on society. The genetic underpinnings of gallstone disease remain incompletely understood. We aimed to identify genetic associations with gallstone disease using publicly available data from the UK Biobank and two large Danish cohorts. We extracted genetic associations with gallstone disease from the Global Biobank Engine (GBE), an online browser of genome‐wide associations in UK Biobank participants (14,940 cases and 322,268 controls). Significant associations (P < 5 × 10–8) were retested in two Copenhagen cohorts (comprising 1,522 cases and 18,266 controls). In the Copenhagen cohorts, we also tested whether a genetic risk score was associated with gallstone disease and whether individual gallstone loci were associated with plasma levels of lipids, lipoproteins, and liver enzymes. We identified 19 loci to be associated with gallstone disease in the GBE. Of these, 12 were replicated in the Copenhagen cohorts, including six previously unknown loci (in hepatocyte nuclear factor 4 alpha [HNF4A], fucosyltransferase 2, serpin family A member 1 [SERPINA1], jumonji domain containing 1C, AC074212.3, and solute carrier family 10A member 2 [SLC10A2]) and six known loci (in adenosine triphosphate binding cassette subfamily G member 8 [ABCG8], sulfotransferase family 2A member 1, cytochrome P450 7A1, transmembrane 4 L six family member 4, ABCB4, and tetratricopeptide repeat domain 39B). Five of the gallstone associations are protein‐altering variants, and three (HNF4A p.Thr139Ile, SERPINA1 p.Glu366Lys, and SLC10A2 p.Pro290Ser) conferred per‐allele odds ratios for gallstone disease of 1.30‐1.36. Individuals with a genetic risk score >2.5 (prevalence 1%) had a 5‐fold increased risk of gallstones compared to those with a score <1.0 (11%). Of the 19 lithogenic loci, 11 and ten exhibited distinct patterns of association with plasma levels of lipids and liver enzymes, respectively. Conclusion: We identified six susceptibility loci for gallstone disease.

Aims Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR). Methods and results Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10−6 to 8.0 × 10−9), with lower risk of MI (P-trend 0.04–0.002) and lower risk of cardiovascular mortality (P-trend 0.005–0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane. Conclusion This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.