Population-specific imputations identify a deleterious coding variant in ABCA6 associated with cholesterol levels: The Genome of the Netherlands. C. M. Van Duijn1, E. M. van Leeuwen1, M. A. Swertz2,3, D. I. Boomsma4, P. E. Slagboom5, G. B. van Ommen6, C. Wijmenga3, P. I. W. de Bakker7,8 on behalf of the CHARGE lipids WG and the Genome of the Netherlands consortium 1) Epidemiology, Erasmus MC, Rotterdam, Zuid Holland, Netherlands; 2) University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands; 3) University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands; 4) Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands; 5) Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 6) Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; 7) Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; 8) Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

   Genome-wide association studies (GWAS) have identified a large number of loci associated with blood lipid levels and there is no evidence that this approach has reached its limits. Despite the fact that rare functional variants are known to play a major role in lipid metabolism for long, there has been a lack of success finding such variants in population-based studies. The power of searches for rare functional variants may improve by the use of reference sets based on next generation sequencing (NGS) specific to distinct populations. This allows a better quality imputation of rare variants in particular those of which the frequency is increased within a specific population. The Genome of the Netherlands (GoNL) project led to a reference for the Dutch population, based on NGS in 250 parent-offspring trios (13x coverage). Nine large Dutch epidemiological cohorts imputed with the GoNL reference panel and conducted a GWAS on high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (TC) and triglyceride (TG) levels. Meta-analysis comprised around 35,000 samples and revealed both rare (minor allele frequency (MAF) < 0.05) and common variants (MAF >= 0.05) associated with HDL (N=60 variants), LDL (N=142 variants), TC (N=134 variants) and TG (N=16 variants) in known and novel loci . A comparison of allele frequencies shows that these variants are more rare than those identified by Teslovich et al. and Willer et al. In addition, we replicated the majority of the lipid loci described by Teslovich et al. and Willer et al. despite a sample size of about 20% of the other studies. We replicated 4 novel loci by association analysis in cohorts from the CHARGE consortium which used the 1000 Genomes reference panel (Phase 1 integrated release v3, April 2012). Among the novel replicated loci is rs77542162 for both LDL (Ntotal=57,593, p-value=1.33E-12) and TC (Ntotal=65,305, p-value=7.31E-11). This exonic variant, which is predicted to be damaging, is located on chromosome 17 within the ABCA6 gene (ATP-binding cassette, sub-family A (ABC1), member 6). The frequency of this variant is 3.65 fold enriched in the GoNL reference panel as compared to the 1000 Genomes reference panel. The effect size of this variant (0.135 for LDL and 0.140 for TC) is very similar to those observed for other well-known lipid genes, such as LDLR and CETP. This suggest that next generation sequencing effort may yield clinically relevant findings.

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