@article {7661, title = {Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer{\textquoteright}s disease.}, journal = {Ann Clin Transl Neurol}, volume = {5}, year = {2018}, month = {2018 Apr}, pages = {406-417}, abstract = {

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer{\textquoteright}s disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95\% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).

Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

}, issn = {2328-9503}, doi = {10.1002/acn3.537}, author = {Vardarajan, Badri N and Barral, Sandra and Jaworski, James and Beecham, Gary W and Blue, Elizabeth and Tosto, Giuseppe and Reyes-Dumeyer, Dolly and Medrano, Martin and Lantigua, Rafael and Naj, Adam and Thornton, Timothy and DeStefano, Anita and Martin, Eden and Wang, Li-San and Brown, Lisa and Bush, William and van Duijn, Cornelia and Goate, Allison and Farrer, Lindsay and Haines, Jonathan L and Boerwinkle, Eric and Schellenberg, Gerard and Wijsman, Ellen and Pericak-Vance, Margaret A and Mayeux, Richard and Wang, Li-San} } @article {7810, title = {Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer{\textquoteright}s disease.}, journal = {Ann Clin Transl Neurol}, volume = {5}, year = {2018}, month = {2018 Jul}, pages = {832-842}, abstract = {

Objective: The genetic bases of Alzheimer{\textquoteright}s disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer{\textquoteright}s disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer{\textquoteright}s Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 {\texttimes} 10; OR: 36.2 [95\% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer{\textquoteright}s disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer{\textquoteright}s disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer{\textquoteright}s disease in a large whole-exome study of unrelated cases and controls.

}, issn = {2328-9503}, doi = {10.1002/acn3.582}, author = {Raghavan, Neha S and Brickman, Adam M and Andrews, Howard and Manly, Jennifer J and Schupf, Nicole and Lantigua, Rafael and Wolock, Charles J and Kamalakaran, Sitharthan and Petrovski, Slave and Tosto, Giuseppe and Vardarajan, Badri N and Goldstein, David B and Mayeux, Richard} } @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} } @article {8794, title = {Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer{\textquoteright}s disease.}, journal = {Alzheimers Dement}, year = {2021}, month = {2021 Jun 20}, abstract = {

INTRODUCTION: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer{\textquoteright}s disease (AD) are inconsistent.

METHODS: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O.

RESULTS: Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L missense variant (rs28709356; minor allele frequency =~0.002; P~=~7.3 {\texttimes} 10 ) as well as with MT-ND4L in a gene-based test (P~=~6.71 {\texttimes} 10 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P~=~2.7 {\texttimes} 10 ). The expression of TAMM41 was lower in AD cases than controls (P~=~.00046) or mild cognitive impairment cases (P~=~.03).

DISCUSSION: Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.

}, issn = {1552-5279}, doi = {10.1002/alz.12396}, author = {Zhang, Xiaoling and Farrell, John J and Tong, Tong and Hu, Junming and Zhu, Congcong and Wang, Li-San and Mayeux, Richard and Haines, Jonathan L and Pericak-Vance, Margaret A and Schellenberg, Gerard D and Lunetta, Kathryn L and Farrer, Lindsay A} }