A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease

The genetic architecture of Alzheimer's disease (AD) is only partially understood. We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ance...

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Published in:Alzheimer's & dementia 2019-03, Vol.15 (3), p.441-452
Main Authors: Zhang, Xiaoling, Ma, Yiyi, Lancour, Daniel, Farrell, John J., Chung, Jaeyoon, Dinh, Huyen, Doddapeneni, Harsha, English, Adam, Gibbs, Richard A., Han, Yi, Jayaseelan, Joy, Kalra, Divya, Khan, Ziad, Lee, Sandra, Liu, Yue, Muzny, Donna, Nasser, Waleed, White, Simon, Worley, Kim, Zhu, Yiming, Beiser, Alexa, Chen, Yuning, Cupples, L. Adrienne, DeStefano, Anita, Dupuis, Josee, Farrell, John, Farrer, Lindsay, Lin, Honghuang, Sarnowski, Chloe, Choi, Seung Hoan, Gabriel, Stacey, Butkiewicz, Mariusz, Haines, Jonathan, Song, Yeunjoo, Barral, Sandra, Reitz, Christiane, Reyes, Dolly, Tosto, Giuseppe, Vardarajan, Badri, Amad, Shahzad, Amin, Najaf, Ikram, M. Afran, van Duijn, Cornelia, Vanderspek, Ashley, Schmidt, Helena, Goate, Alison, Marcora, Edoardo, Foroud, Tatiana, Feolo, Michael, Launer, Lenore J., Bennett, David A., Xia, Li Charlie, Beecham, Gary, Hamilton-Nelson, Kara, Jaworski, James, Martin, Eden, Pericak-Vance, Margaret, Rajabli, Farid, Schmidt, Michael, Cantwell, Laura, Childress, Micah, Chou, Yi-Fan, Cweibel, Rebecca, Leung, Yuk Yee, Lin, Han-Jen, Malamon, John, Naj, Adam, Valladares, Otto, Wang, Li-San, Wang, Weixin, Zhang, Nancy, Boerwinkle, Eric, Bressler, Jan, Fornage, Myriam, Jian, Xueqiu, Liu, Xiaoming, Blue, Elizabeth, Brown, Lisa, Day, Tyler, Dorschner, Michael, Horimoto, Andrea R., Nato, Alejandro Q., Navas, Pat, Nguyen, Hiep, Rice, Kenneth, Sohi, Harkirat, Thornton, Timothy, Tsuang, Debby, Cruchaga, Carlos, Fulton, Robert S., Koboldt, Daniel C., Larson, David E., Waligorski, Jason, Wilson, Richard K., Haines, Jonathan L., Pericak-Vance, Margaret A., Lunetta, Kathryn L.
Format: Article
Language:English
Subjects:
Age of Onset
Aged
Aged, 80 and over
Alzheimer Disease - epidemiology
Alzheimer Disease - genetics
Association study
Case-Control Studies
Caspase 7 - genetics
Enriched case-control
Gene-based analyses
Genetic Predisposition to Disease
Genome-wide association studies
Genome-Wide Association Study
Hispanic or Latino - genetics
Humans
Mutation, Missense
White People - genetics
Whole exome sequencing
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Summary:The genetic architecture of Alzheimer's disease (AD) is only partially understood. We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10−10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10−10). Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
ISSN:1552-5260
1552-5279
DOI:10.1016/j.jalz.2018.10.005