title: Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.
abstract: Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana University Network Science Institute, Bloomington, IN, USA.
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana University Network Science Institute, Bloomington, IN, USA.
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Internal Medicine, Preliminary Medicine Residency, St. Vincent Indianapolis, Indianapolis, IN, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Ramanan
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Lai
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana University Network Science Institute, Bloomington, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Lane
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Murrell
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Hall
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Unverzagt
authors.affiliation: Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: Olusegun
authors.initials: O
authors.lastname: Baiyewu
authors.affiliation: Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: Adesola
authors.initials: A
authors.lastname: Ogunniyi
authors.affiliation: Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: Oye
authors.initials: O
authors.lastname: Gureje
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Behavioral Health Service, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
authors.forename: Mitchel A
authors.initials: MA
authors.lastname: Kling
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.|Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
authors.forename: P Murali
authors.initials: PM
authors.lastname: Doraiswamy
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.|Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.|Pharmacometabolomics Center, Duke University, Durham, NC, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Kaddurah-Daouk
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana University Center for Aging Research, Indianapolis, IN, USA.|Regenstrief Institute Inc., Indianapolis, IN, USA.
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Hendrie
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana University Network Science Institute, Bloomington, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D044383:Black People / Q000235:genetics*; D015331:Cohort Studies; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007196:Indiana; D008137:Longitudinal Studies; D008297:Male; D009549:Nigeria; D011446:Prospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D006710:Homocysteine; D003541:Cystathionine beta-Synthase
keywords: African Continental Ancestry Group; CD2-associated protein; cystathionine beta-synthase; genome-wide association study; homocysteine; metabolic networks and pathways; metabolomics