Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians

Article type: Research Article

Authors: Kim, Sungeun^{a; b; c; d; *} | Nho, Kwangsik^{a; b; c; d} | Ramanan, Vijay K.^{a; b; e; f} | Lai, Dongbing^e | Foroud, Tatiana M.^{b; c; d; e} | Lane, Katie^g | Murrell, Jill R.^{b; h} | Gao, Sujuan^{b; g} | Hall, Kathleen S.ⁱ | Unverzagt, Frederick W.ⁱ | Baiyewu, Olusegun^j | Ogunniyi, Adesola^k | Gureje, Oye^j | Kling, Mitchel A.^{l; m} | Doraiswamy, P. Murali^{n; o} | Kaddurah-Daouk, Rima^{n; o; p} | Hendrie, Hugh C.^{i; q; r} | Saykin, Andrew J.^{a; b; c; d; e; *}

Affiliations: [a] Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA | [b] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA | [c] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Indiana University Network Science Institute, Bloomington, IN, USA | [e] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA | [f] Department of Internal Medicine, Preliminary Medicine Residency, St. Vincent Indianapolis, Indianapolis, IN, USA | [g] Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA | [h] Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA | [i] Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA | [j] Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria | [k] Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria | [l] Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [m] Behavioral Health Service, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA | [n] Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA | [o] Duke Institute for Brain Sciences, Duke University, Durham, NC, USA | [p] Pharmacometabolomics Center, Duke University, Durham, NC, USA | [q] Indiana University Center for Aging Research, Indianapolis, IN, USA | [r] Regenstrief Institute Inc., Indianapolis, IN, USA

Correspondence: [*] Correspondence to: Sungeun Kim, PhD and Andrew J. Saykin, PsyD, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, IU Health Neuroscience Center, Suite 4100, 355 West 16th Street, Indianapolis, IN 46202, USA. Tel.: +1 317 963 7505; Fax: +1 317 963 7547; E-mail: sk31@iupui.edu (Sungeun Kim); Tel.: +1 317 963 7501; Fax: +1 317 963 7547; E-mail: asaykin@iupui.edu (Andrew J. Saykin).

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.

Keywords: African Continental Ancestry Group, CD2-associated protein, cystathionine beta-synthase, genome-wide association study, homocysteine, metabolic networks and pathways, metabolomics

DOI: 10.3233/JAD-150651

Journal: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 991-1003, 2016