Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome.
The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86 × 10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63 × 10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37 × 10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52 × 10(-8), Pmeta=7.82 × 10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: ayeleft@mail.nih.gov.
Fasil
F
Tekola-Ayele
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Ayo P
AP
Doumatey
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Daniel
D
Shriner
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Amy R
AR
Bentley
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Guanjie
G
Chen
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Jie
J
Zhou
University of Lagos, Lagos, Nigeria.
Olufemi
O
Fasanmade
University of Lagos, Lagos, Nigeria.
Thomas
T
Johnson
University of Nigeria Teaching Hospital, Enugu, Nigeria.
Johnnie
J
Oli
University of Nigeria Teaching Hospital, Enugu, Nigeria.
Godfrey
G
Okafor
University of Science and Technology, Department of Medicine, Kumasi, Ghana.
Benjami A
BA
Eghan
University of Science and Technology, Department of Medicine, Kumasi, Ghana.
Kofi
K
Agyenim-Boateng
Department of Epidemiology and Public Health, School of Medicine, University of Maryland, Baltimore, MD, USA.
Clement
C
Adebamowo
University of Ghana Medical School, Department of Medicine, Accra, Ghana.
Albert
A
Amoah
University of Science and Technology, Department of Medicine, Kumasi, Ghana.
Joseph
J
Acheampong
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Adebowale
A
Adeyemo
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: rotimic@mail.nih.gov.
Charles N
CN
Rotimi
D000328:Adult; D044383:Black People; D001794:Blood Pressure; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005869:Ghana; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000235:genetics; D006801:Humans; D007630:Kenya; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009549:Nigeria; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D044465:White People; D051178:alpha Catenin / Q000235:genetics*; D001741:Black or African American
C512815:CA10 protein, human; C506642:CETP protein, human; C441963:CTNNA3 protein, human; D053480:Cholesterol Ester Transfer Proteins; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D009419:Nerve Tissue Proteins; C088730:RALY protein, human; D014280:Triglycerides; D051178:alpha Catenin; C557409:KSR2 protein, human; D017346:Protein Serine-Threonine Kinases; C548261:LPL protein, human; D008071:Lipoprotein Lipase
African ancestry; Genome-wide association study; Metabolic syndrome; Pleiotropy