@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 {7847, title = {Rare loss of function variants in candidate genes and risk of colorectal cancer.}, journal = {Hum Genet}, year = {2018}, month = {2018 Sep 28}, abstract = {

Although ~ 25\% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20\% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20\% of cases vs. 11.5\% of controls with >= 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18\% had a PDV, significantly different from 11.5\% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

}, issn = {1432-1203}, doi = {10.1007/s00439-018-1938-4}, author = {Rosenthal, Elisabeth A and Shirts, Brian H and Amendola, Laura M and Horike-Pyne, Martha and Robertson, Peggy D and Hisama, Fuki M and Bennett, Robin L and Dorschner, Michael O and Nickerson, Deborah A and Stanaway, Ian B and Nassir, Rami and Vickers, Kathy T and Li, Christopher and Grady, William M and Peters, Ulrike and Jarvik, Gail P} }