Browsing by Author "Ogunniyi, Adesola"
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Item A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry(Public Library of Science, 2022-07-05) Rajabli, Farid; Beecham, Gary W.; Hendrie, Hugh C.; Baiyewu, Olusegun; Ogunniyi, Adesola; Gao, Sujuan; Kushch, Nicholas A.; Lipkin-Vasquez, Marina; Hamilton-Nelson, Kara L.; Young, Juan I.; Dykxhoorn, Derek M.; Nuytemans, Karen; Kunkle, Brian W.; Wang, Liyong; Jin, Fulai; Liu, Xiaoxiao; Feliciano-Astacio, Briseida E.; Alzheimer’s Disease Sequencing Project; Alzheimer’s Disease Genetic Consortium; Schellenberg, Gerard D.; Dalgard, Clifton L.; Griswold, Anthony J.; Byrd, Goldie S.; Reitz, Christiane; Cuccaro, Michael L.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Psychiatry, School of MedicineAfrican descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.Item APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba(Cambridge University Press, 2014-06) Hendrie, Hugh C.; Murrell, Jill; Baiyewu, Olusegun; Lane, Kathleen A.; Purnell, Christianna; Ogunniyi, Adesola; Unverzagt, Frederick W.; Hall, Kathleen; Callahan, Christopher M.; Saykin, Andrew J.; Gureje, Oye; Hake, Ann; Foroud, Tatiana; Gao, Sujuan; Department of Psychiatry, IU School of MedicineBackground There is little information on the association of the APOEe4 allele and AD risk in African populations. In previous analyses from the Indianapolis-Ibadan dementia project, we have reported that APOE ε4 increased the risk for Alzheimer’s disease (AD) in African Americans but not in Yoruba. This study represents a replication of this earlier work using enriched cohorts and extending the analysis to include cognitive decline. Methods In this longitudinal study of two community dwelling cohorts of elderly Yoruba and African Americans, APOE genotyping was conducted from blood samples taken on or before 2001 (1,871 African Americans & 2,200 Yoruba). Mean follow up time was 8.5 years for African Americans and 8.8 years for Yoruba. The effects of heterozygosity or homozygosity of ε4 and of the possession of e4 on time to incident AD and on cognitive decline were determined using Cox’s proportional hazards regression and mixed effects models. Results After adjusting for covariates, one or two copies of the APOE ε4 allele were significant risk factors for incident AD (p < 0.0001) and cognitive decline in the African-American population (p < 0001). In the Yoruba, only homozygosity for APOE ε4 was a significant risk factor for AD (p = 0.0002) but not for cognitive decline (p = 0.2346), however, possession of an e4 allele was significant for both incident AD (p = 0.0489) and cognitive decline (p = 0.0425). Conclusions In this large longitudinal comparative study, APOE ε4 had a significant, but weaker, effect on incident AD and on cognitive decline in Yoruba than in African Americans. The reasons for these differences remain unclear.Item Dementia incidence declined in African-Americans but not in Yoruba(Elsevier, 2016-03) Gao, Sujuan; Ogunniyi, Adesola; Hall, Kathleen S.; Baiyewu, Olesegun; Unverzagt, Frederick W.; Lane, Kathleen A.; Murrell, Jill R.; Gureje, Oye; Hendrie, Hugh C.; Department of Biostatistics, Richard M. Fairbanks School of Public HealthINTRODUCTION: To compare dementia incidence of African-American and Yoruba cohorts aged ≥70 years enrolled in 1992 and 2001. METHODS: African-Americans residing in Indianapolis and Yoruba in Ibadan, Nigeria without dementia were enrolled in 1992 and 2001 and evaluated every 2-3 years until 2009. The cohorts consist of 1440 African-Americans, 1774 Yoruba in 1992 and 1835 African-Americans and 1895 Yoruba in the 2001 cohorts aged ≥70 years. RESULTS: In African-Americans, dementia and Alzheimer's disease (AD) incidence rates were significantly lower in 2001 than 1992 for all age groups except the oldest group. The overall standardized annual dementia incidence rates were 3.6% (95% confidence interval [CI], 3.2%-4.1%) in the 1992 cohort and 1.4% (95% CI, 1.2%-1.7%) in the 2001 cohort. There was no significant difference in dementia or AD incidence between the Yoruba cohorts. DISCUSSION: Future research is needed to explore the reasons for the differential changes in incidence rates in these two populations.Item Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry(Wiley, 2024) Ray, Nicholas R.; Kunkle, Brian W.; Hamilton-Nelson, Kara; Kurup, Jiji T.; Rajabli, Farid; Qiao, Min; Vardarajan, Badri N.; Cosacak, Mehmet I.; Kizil, Caghan; Jean-Francois, Melissa; Cuccaro, Michael; Reyes-Dumeyer, Dolly; Cantwell, Laura; Kuzma, Amanda; Vance, Jeffery M.; Gao, Sujuan; Hendrie, Hugh C.; Baiyewu, Olusegun; Ogunniyi, Adesola; Akinyemi, Rufus O.; Alzheimer’s Disease Genetics Consortium; Lee, Wan-Ping; Martin, Eden R.; Wang, Li-San; Beecham, Gary W.; Bush, William S.; Xu, Wanying; Jin, Fulai; Wang, Liyong; Farrer, Lindsay A.; Haines, Jonathan L.; Byrd, Goldie S.; Schellenberg, Gerard D.; Mayeux, Richard; Pericak-Vance, Margaret A.; Reitz, Christiane; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthIntroduction: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. Methods: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. Results: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. Discussion: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. Highlights: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at p < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.Item The fourth apolipoprotein E haplotype found in the Yoruba of Ibadan(Wiley, 2006-06) Murrell, Jill R.; Price, Brandon M.; Baiyewu, Olusegun; Gureje, Oye; Deeg, Mark; Hendrie, Hugh; Ogunniyi, Adesola; Hall, Kathleen; Department of Medicine, IU School of MedicineItem Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.(IOS Press, 2015) Kim, Sungeun; Nho, Kwangsik; Ramanan, Vijay K.; Lai, Dongbing; Foroud, Tatiana M.; Lane, Katie; Murrell, Jill R.; Gao, Sujuan; Hall, Kathleen S.; Unverzagt, Frederick W.; Baiyewu, Olusegun; Ogunniyi, Adesola; Gureje, Oye; Kling, Mitchel A.; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima; Hendrie, Hugh C.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, IU School of MedicinePlasma 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.Item Homocysteine levels and dementia risk in Yoruba and African Americans(Elsevier, 2013) Hendrie, Hugh C.; Baiyewu, Olusegun; Lane, Kathleen A.; Purnell, Christianna; Gao, Sujuan; Hake, Ann; Ogunniyi, Adesola; Gureje, Oye; Unverzagt, Frederick W.; Murrell, Jill; Deeg, Mark A.; Hall, Kathleen; Psychiatry, School of MedicineBackground: High levels of homocysteine have been associated with increased risk for dementia although results have been inconsistent. There are no reported studies from the developing world including Africa. Methods: In this longitudinal study of two community-dwelling cohorts of elderly Yoruba and African Americans, levels of homocysteine, vitamin B12 and folate were measured from blood samples taken in 2001. These levels were compared in two groups, participants who developed incident dementia in the follow-up until 2009 (59 Yoruba and 101 African Americans) and participants who were diagnosed as cognitively normal or in the good performance category at their last follow-up (760 Yoruba and 811 African Americans). Homocysteine levels were divided into quartiles for each site. Results: After adjusting for age, education, possession of ApoE, smoking, and time of enrollment the higher quartiles of homocysteine were associated with a non-significant increase in dementia risk in the Yoruba (homocysteine quartile 4 vs. 1 OR: 2.19, 95% CI 0.95-5.07, p = 0.066). For the African Americans, there was a similar but non-significant relationship between higher homocysteine levels and dementia risk. There were no significant relationships between levels of vitamin B12 and folate and incident dementia in either site although folate levels were lower and vitamin B12 levers were higher in the Yoruba than in the African Americans. Conclusions: Increased homocysteine levels were associated with a similar but non-significant increase in dementia risk for both Yoruba and African Americans despite significant differences in folate levels between the two sites.Item Obesity and 10-Year Mortality in Very Old African Americans and Yoruba-Nigerians: Exploring the Obesity Paradox(Oxford University Press, 2014-09) Clark, Daniel O.; Gao, Sujuan; Lane, Kathleen A.; Callahan, Christopher M.; Baiyewu, Olusegun; Ogunniyi, Adesola; Hendrie, Hugh C.; Department of Medicine, IU School of MedicineBackground. To compare the effect of obesity and related risk factors on 10-year mortality in two cohorts of older adults of African descent; one from the United States and one from Nigeria. Methods. Study participants were community residents aged 70 or older of African descent living in Indianapolis, Indiana (N = 1,269) or Ibadan, Nigeria (1,197). We compared survival curves between the two cohorts by obesity class and estimated the effect of obesity class on mortality in Cox proportional hazards models controlling for age, gender, alcohol use, and smoking history, and the cardiometabolic biomarkers blood pressure, triglycerides, high-density lipoprotein, low-density lipoprotein, and C-reactive protein. Results. We found that underweight was associated with an increased risk of death in both the Yoruba (hazards ratio = 1.35, 95% confidence interval: 1.12–1.63) and African American samples (hazards ratio = 2.49, 95% confidence interval: 1.40–4.43) compared with those with normal weight. The overweight and obese participants in both cohorts experienced survival similar to the normal weight participants. Controlling for cardiometabolic biomarkers had little effect on the obesity-specific hazard ratios in either cohort. Conclusions. Despite significant differences across these two cohorts in terms of obesity and biomarker levels, overall 10-year survival and obesity class–specific survival were remarkably similar.Item Statin Use, Incident Dementia and Alzheimer Disease in Elderly African Americans(International Society on Hypertension in Blacks, 2015) Hendrie, Hugh C.; Hake, Ann; Lane, Kathleen; Purnell, Christianna; Unverzagt, Frederick; Smith-Gamble, Valerie; Murrell, Jill; Ogunniyi, Adesola; Baiyewu, Olusegun; Callahan, Chris; Saykin, Andrew J.; Taylor, Stanley; Hall, Kathleen; Gao, Su; Department of Neurology, IU School of MedicineOBJECTIVE: To investigate the association between statin use, incident dementia, and Alzheimer disease (AD) in a prospective elderly African American cohort. DESIGN: Two stage design with a screening interview followed by a comprehensive in-home assessment conducted over an eight-year period. Diagnoses of incident AD and dementia were made by consensus. Statin use was collected at each evaluation. Measurements of low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and APOE genotype were obtained from baseline blood samples. Logistic regression models were used to test the association of statin use on incident dementia and AD and its possible association with lipid and CRP levels. SETTING: Indianapolis, Indiana. PARTICIPANTS: From an original cohort of 2629 participants, a subsample of 974 African Americans aged >70 years with normal cognition, at least one follow up evaluation, complete statin information, and biomarker availability were included. MAIN OUTCOME MEASURES: Incident dementia and incident AD. RESULTS: After controlling for age at diagnosis, sex, education level, presence of the APOE ε4 allele and history of stroke for the incident dementia model, baseline use of statins was associated with a significantly decreased risk of incident dementia (OR=.44, P=.029) and incident AD (OR=.40, P=.029). The significant effect of statin use on reduced AD risk and trend for dementia risk was found only for those participants who reported consistent use over the observational period (incident AD: P=.034; incident dementia: P=.061). Additional models found no significant interaction between baseline statin use, baseline LDL, or CRP level and incident dementia/AD. CONCLUSIONS: Consistent use of statin medications during eight years of follow-up resulted in significantly reduced risk for incident AD and a trend toward reduced risk for incident dementia.Item Vascular-brain Injury Progression after Stroke (VIPS) Study: concept for understanding racial and geographic determinants of cognitive decline after stroke(Elsevier, 2020) Sarfo, Fred Stephen; Akinyemi, Rufus; Howard, George; Howard, Virginia J.; Wahab, Kolawole; Cushman, Mary; Levine, Deborah A.; Ogunniyi, Adesola; Unverzagt, Fred; Owolabi, Mayowa; Ovbiagele, Bruce; Psychiatry, School of MedicineCognitive impairment and dementia (CID) are major public health problems with substantial personal, social, and financial burdens. African Americans are at a heightened risk for Vascular Cognitive Impairment (VCI) compared to European Americans. Recent lines of evidence also suggest a high burden of Post-stroke VCI among indigenous Africans. A better understanding of the cause(s) of the racial disparity in CID, specifically VCI, is needed in order to develop strategies to reduce it. We propose and discuss the conceptual framework for a unique tri-population, trans-continental study titled The Vascular brain Injury Progression after Stroke (VIPS) study. The overarching objective of the VIPS Study will be to explore the interplay of multiple factors (racial, geographical, vascular, lifestyle, nutritional, psychosocial and inflammatory) influencing the level and trajectory of post-stroke cognitive outcomes and examine whether differences between indigenous Africans, African Americans and European Americans exist. We hypothesize that differences which might be due to racial factors will be observed in African Americans versus European Americans as well as Indigenous Africans versus European Americans but not in African Americans versus Indigenous Americans; differences due to geographical factors will be observed in Indigenous Americans versus African Americans and Indigenous Africans versus European Americans but not in African Americans versus European Americans. This overarching objective could be accomplished by building upon existing National Institutes of Health investments in the REasons for Geographical And Racial Differences in Stroke (REGARDS) study (based in the United States of America) and the Stroke Investigative Research and educational Network (SIREN) study (based in Sub-Saharan Africa).