Line Skotte1, Anders Koch2, Victor Yakimov2, Sirui Zhou2, Bolette Søborg2, Mikael Andersson2, Sascha W Michelsen2, Johan E Navne2, Jacqueline M Mistry2, Patrick A Dion2, Michael L Pedersen2, Malene L Børresen2, Guy A Rouleau2, Frank Geller2, Mads Melbye2, Bjarke Feenstra1. 1. From the Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark (L.S., A.K., V.Y., B.S., M.A., S.W.M., J.E.N., J.M.M., M.L.B., F.G., M.M., B.F.); Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada (S.Z., P.A.D., G.A.R.); Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (P.A.D., G.A.R.); Département de Médecine, Faculté de Médecine, Université de Montréal, Quebec, Canada (S.Z.); Greenland Center for Health Research, Institute of Nursing and Health Science, University of Greenland, Nuuk, Greenland (M.L.P.); Department of Clinical Medicine, University of Copenhagen, Denmark (M.M.); and Department of Medicine, Stanford University School of Medicine, California (M.M.). fee@ssi.dk lik@ssi.dk. 2. From the Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark (L.S., A.K., V.Y., B.S., M.A., S.W.M., J.E.N., J.M.M., M.L.B., F.G., M.M., B.F.); Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada (S.Z., P.A.D., G.A.R.); Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (P.A.D., G.A.R.); Département de Médecine, Faculté de Médecine, Université de Montréal, Quebec, Canada (S.Z.); Greenland Center for Health Research, Institute of Nursing and Health Science, University of Greenland, Nuuk, Greenland (M.L.P.); Department of Clinical Medicine, University of Copenhagen, Denmark (M.M.); and Department of Medicine, Stanford University School of Medicine, California (M.M.).
Abstract
BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10-15, P=4.02×10-19, and P=7.92×10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.
BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10-15, P=4.02×10-19, and P=7.92×10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.
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