CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders

Line Skotte; Anders Koch; Victor Yakimov; Sirui Zhou; Bolette Søborg; Mikael Andersson; Sascha W. Michelsen; Johan E. Navne; Jacqueline M. Mistry; Patrick A. Dion; Michael L. Pedersen; Malene L. Børresen; Guy A. Rouleau; Frank Geller; Mads Melbye; Bjarke Feenstra

doi:10.1161/circgenetics.116.001618

CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders

Line Skotte^*, Anders Koch, Victor Yakimov, Sirui Zhou, Bolette Søborg, Mikael Andersson, Sascha W. Michelsen, Johan E. Navne, Jacqueline M. Mistry, Patrick A. Dion, Michael L. Pedersen, Malene L. Børresen, Guy A. Rouleau, Frank Geller, Mads Melbye, Bjarke Feenstra

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

17 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	e001618
Tidsskrift	Circulation: Cardiovascular Genetics
Vol/bind	10
Udgave nummer	3
Antal sider	15
ISSN	1942-325X
DOI	https://doi.org/10.1161/circgenetics.116.001618
Status	Udgivet - jun. 2017

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10.1161/circgenetics.116.001618

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Skotte, L., Koch, A., Yakimov, V., Zhou, S., Søborg, B., Andersson, M., Michelsen, S. W., Navne, J. E., Mistry, J. M., Dion, P. A., Pedersen, M. L., Børresen, M. L., Rouleau, G. A., Geller, F., Melbye, M., & Feenstra, B. (2017). CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders. Circulation: Cardiovascular Genetics, 10(3), Artikel e001618. https://doi.org/10.1161/circgenetics.116.001618

Skotte, L, Koch, A, Yakimov, V, Zhou, S, Søborg, B, Andersson, M, Michelsen, SW, Navne, JE, Mistry, JM, Dion, PA, Pedersen, ML, Børresen, ML, Rouleau, GA, Geller, F, Melbye, M & Feenstra, B 2017, 'CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders', Circulation: Cardiovascular Genetics, bind 10, nr. 3, e001618. https://doi.org/10.1161/circgenetics.116.001618

@article{cd63be0328224d74b5834106d99480b7,

title = "CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders",

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.",

keywords = "fatty acid, unsaturated, Genome-Wide Association Study, Inuit, metabolomics, mutation, missense",

author = "Line Skotte and Anders Koch and Victor Yakimov and Sirui Zhou and Bolette S{\o}borg and Mikael Andersson and Michelsen, {Sascha W.} and Navne, {Johan E.} and Mistry, {Jacqueline M.} and Dion, {Patrick A.} and Pedersen, {Michael L.} and B{\o}rresen, {Malene L.} and Rouleau, {Guy A.} and Frank Geller and Mads Melbye and Bjarke Feenstra",

year = "2017",

month = jun,

doi = "10.1161/circgenetics.116.001618",

language = "English",

volume = "10",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

number = "3",

}

TY - JOUR

T1 - CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders

AU - Skotte, Line

AU - Koch, Anders

AU - Yakimov, Victor

AU - Zhou, Sirui

AU - Søborg, Bolette

AU - Andersson, Mikael

AU - Michelsen, Sascha W.

AU - Navne, Johan E.

AU - Mistry, Jacqueline M.

AU - Dion, Patrick A.

AU - Pedersen, Michael L.

AU - Børresen, Malene L.

AU - Rouleau, Guy A.

AU - Geller, Frank

AU - Melbye, Mads

AU - Feenstra, Bjarke

PY - 2017/6

Y1 - 2017/6

N2 - 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.

AB - 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.

KW - fatty acid, unsaturated

KW - Genome-Wide Association Study

KW - Inuit

KW - metabolomics

KW - mutation, missense

U2 - 10.1161/circgenetics.116.001618

DO - 10.1161/circgenetics.116.001618

M3 - Journal article

C2 - 28611031

AN - SCOPUS:85021076742

SN - 1942-325X

VL - 10

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 3

M1 - e001618

ER -

CPT1A Missense Mutation Associated with Fatty Acid Metabolism and Reduced Height in Greenlanders

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