Browsing by Author "Qiao, Min"

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    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 Health
    Introduction: 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.
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    Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease
    (Wiley, 2023) Qiao, Min; Lee, Annie J.; Reyes-Dumeyer, Dolly; Tosto, Giuseppe; Faber, Kelley; Goate, Alison; Renton, Alan; Chao, Michael; Boeve, Brad; Cruchaga, Carlos; Pericak-Vance, Margaret; Haines, Jonathan L.; Rosenberg, Roger; Tsuang, Debby; Sweet, Robert A.; Bennett, David A.; Wilson, Robert S.; Foroud, Tatiana; Mayeux, Richard; Vardarajan, Badri N.; Medical and Molecular Genetics, School of Medicine
    Objective: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers. Results: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older. Interpretation: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.