title: Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.
abstract: Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.
authors.affiliation: 1] Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA [2] Molecular Biology Institute at UCLA, Los Angeles, California 90095, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Ko
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Elina
authors.initials: E
authors.lastname: Nikkola
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Prasad M V Linga
authors.initials: PM
authors.lastname: Reddy
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.affiliation: 1] Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA [2] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA [3] Bioinformatics Interdepartmental Program, UCLA, Los Angeles, California 90095, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.affiliation: Bioinformatics Interdepartmental Program, UCLA, Los Angeles, California 90095, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: 1] Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico [2] Instituto de Investigaciones Biomédicas de la UNAM, 04510 04510 Mexico City, Mexico.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rodriguez-Guillen
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico.
authors.forename: Ivette C
authors.initials: IC
authors.lastname: Bautista
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico.
authors.forename: Olimpia
authors.initials: O
authors.lastname: Arellano-Campos
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Muñoz-Hernández
authors.affiliation: National Institute for Health and Welfare, 00271 Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: 1] National Institute for Health and Welfare, 00271 Helsinki, Finland [2] Department of Public Health, Hjelt Institute, University of Helsinki, 00014 Helsinki, Finland [3] Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: National Institute for Health and Welfare, 00271 Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.affiliation: National Institute for Health and Welfare, 00271 Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: National Institute for Health and Welfare, 00271 Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Heliövaara
authors.affiliation: 1] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland [2] Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20520 Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Raitakari
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, 33100 Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: 1] National Institute for Health and Welfare, 00271 Helsinki, Finland [2] Folkhälsan Research Center, University of Helsinki, 00290 Helsinki, Finland [3] Department of General Practice and Primary Health Care, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.affiliation: 1] National Institute for Health and Welfare, 00271 Helsinki, Finland [2] Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland [3] University of Tartu, Estonian Genome Center, 51010 Tartu, Estonia.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, California 90095, USA.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Lohmueller
authors.affiliation: Department of Medicine, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Matikainen
authors.affiliation: Department of Medicine, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico.
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: 1] Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico [2] Instituto de Investigaciones Biomédicas de la UNAM, 04510 04510 Mexico City, Mexico.
authors.forename: Laura
authors.initials: L
authors.lastname: Riba
authors.affiliation: 1] Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico [2] Instituto de Investigaciones Biomédicas de la UNAM, 04510 04510 Mexico City, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusie-Luna
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, 14000 Mexico City, Mexico.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.affiliation: 1] Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA [2] Molecular Biology Institute at UCLA, Los Angeles, California 90095, USA.
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D000328:Adult; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D015228:Hypertriglyceridemia / Q000235:genetics*; D007198:Indians, North American / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008800:Mexico / Q000208:ethnology; D008875:Middle Aged; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D011494:Protein Kinases; C509079:SIK3 protein, human; C548261:LPL protein, human; D008071:Lipoprotein Lipase