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Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets
Author(s) -
Ramos Jairo,
Caywood Laura J.,
Prough Michael B.,
Clouse Jason E.,
Herington Sharlene D.,
Slifer Susan H.,
Fuzzell M. Denise,
Fuzzell Sarada L.,
Hochstetler Sherri D.,
Miskimen Kristy L.,
Main Leighanne R.,
Osterman Michael D.,
Zaman Andrew F.,
Whitehead Patrice L.,
Adams Larry D.,
Laux Renee A.,
Song Yeunjoo E.,
Foroud Tatiana M.,
Mayeux Richard P.,
St. GeorgeHyslop Peter,
Ogrocki Paula K.,
Lerner Alan J.,
Vance Jeffery M.,
Cuccaro Michael L.,
Haines Jonathan L.,
PericakVance Margaret A.,
Scott William K.
Publication year - 2023
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12686
Subject(s) - hazard ratio , disease , allele , single nucleotide polymorphism , genetic association , gene , genetics , chromosome , biology , genome wide association study , cognitive impairment , cognition , proportional hazards model , medicine , genotype , neuroscience , confidence interval
Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI. Methods A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed‐effects models examined association between age and single nucleotide variants (SNVs). Results Three SNVs were significantly associated ( P < 5 × 10 –8 ) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late‐Onset Alzheimer's Disease dataset. Discussion The replicated genome‐wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post‐synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease.