TY  - JOUR
AU  - Ray, Nicholas R
AU  - Kunkle, Brian W
AU  - Hamilton-Nelson, Kara
AU  - Kurup, Jiji T
AU  - Rajabli, Farid
AU  - Qiao, Min
AU  - Vardarajan, Badri N
AU  - Cosacak, Mehmet I
AU  - Kizil, Caghan
AU  - Jean-Francois, Melissa
AU  - Cuccaro, Michael
AU  - Reyes-Dumeyer, Dolly
AU  - Cantwell, Laura
AU  - Kuzma, Amanda
AU  - Vance, Jeffery M
AU  - Gao, Sujuan
AU  - Hendrie, Hugh C
AU  - Baiyewu, Olusegun
AU  - Ogunniyi, Adesola
AU  - Akinyemi, Rufus O
AU  - Lee, Wan-Ping
AU  - Martin, Eden R
AU  - Wang, Li-San
AU  - Beecham, Gary W
AU  - Bush, William S
AU  - Xu, Wanying
AU  - Jin, Fulai
AU  - Wang, Liyong
AU  - Farrer, Lindsay A
AU  - Haines, Jonathan L
AU  - Byrd, Goldie S
AU  - Schellenberg, Gerard D
AU  - Mayeux, Richard
AU  - Pericak-Vance, Margaret A
AU  - Reitz, Christiane
TI  - Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.
JO  - Alzheimer's and dementia
VL  - 20
IS  - 8
SN  - 1552-5260
CY  - Hoboken, NJ
PB  - Wiley
M1  - DZNE-2024-01080
SP  - 5247 - 5261
PY  - 2024
AB  - Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts.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.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.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.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.
KW  - Humans
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: ethnology
KW  - Genome-Wide Association Study
KW  - Genetic Predisposition to Disease: genetics
KW  - Black People: genetics
KW  - Linkage Disequilibrium
KW  - Polymorphism, Single Nucleotide: genetics
KW  - Female
KW  - Male
KW  - Aged
KW  - African Americans (Other)
KW  - African genome Panel (Other)
KW  - Alzheimer's disease (Other)
KW  - genome‐wide association study (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11350055
C6  - pmid:38958117
DO  - DOI:10.1002/alz.13880
UR  - https://pub.dzne.de/record/271868
ER  -