@article {7786, title = {Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer{\textquoteright}s Disease Sequencing Project.}, journal = {Dement Geriatr Cogn Disord}, volume = {45}, year = {2018}, month = {2018}, pages = {1-17}, abstract = {

BACKGROUND/AIMS: The Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer{\textquoteright}s disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

}, issn = {1421-9824}, doi = {10.1159/000485503}, author = {Blue, Elizabeth E and Bis, Joshua C and Dorschner, Michael O and Tsuang, Debby W and Barral, Sandra M and Beecham, Gary and Below, Jennifer E and Bush, William S and Butkiewicz, Mariusz and Cruchaga, Carlos and DeStefano, Anita and Farrer, Lindsay A and Goate, Alison and Haines, Jonathan and Jaworski, Jim and Jun, Gyungah and Kunkle, Brian and Kuzma, Amanda and Lee, Jenny J and Lunetta, Kathryn L and Ma, Yiyi and Martin, Eden and Naj, Adam and Nato, Alejandro Q and Navas, Patrick and Nguyen, Hiep and Reitz, Christiane and Reyes, Dolly and Salerno, William and Schellenberg, Gerard D and Seshadri, Sudha and Sohi, Harkirat and Thornton, Timothy A and Valadares, Otto and van Duijn, Cornelia and Vardarajan, Badri N and Wang, Li-San and Boerwinkle, Eric and Dupuis, Jos{\'e}e and Pericak-Vance, Margaret A and Mayeux, Richard and Wijsman, Ellen M} } @article {7932, title = {A rare missense variant of CASP7 is associated with familial late-onset Alzheimer{\textquoteright}s disease.}, journal = {Alzheimers Dement}, year = {2019}, month = {2019 Jan 03}, abstract = {

INTRODUCTION: The genetic architecture of Alzheimer{\textquoteright}s disease (AD) is only partially understood.

METHODS: 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.

RESULTS: 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~{\texttimes}~10) which improved when combined with results from stage 2 data sets (P~=~1.92~{\texttimes}~10).

DISCUSSION: 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 = {1552-5279}, doi = {10.1016/j.jalz.2018.10.005}, author = {Zhang, Xiaoling and Zhu, Congcong and Beecham, Gary and Vardarajan, Badri N and Ma, Yiyi and Lancour, Daniel and Farrell, John J and Chung, Jaeyoon and Mayeux, Richard and Haines, Jonathan L and Schellenberg, Gerard D and Pericak-Vance, Margaret A and Lunetta, Kathryn L and Farrer, Lindsay A} }