Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets

Jairo Ramos; Laura J Caywood; Michael B Prough; Jason E Clouse; Sharlene D Herington; Susan H Slifer; M Denise Fuzzell; Sarada L Fuzzell; Sherri D Hochstetler; Kristy L Miskimen; Leighanne R Main; Michael D Osterman; Andrew F Zaman; Patrice L Whitehead; Larry D Adams; Renee A Laux; Yeunjoo E Song; Tatiana M Foroud; Richard P Mayeux; Peter St George-Hyslop; Paula K Ogrocki; Alan J Lerner; Jeffery M Vance; Michael L Cuccaro; Jonathan L Haines; Margaret A Pericak-Vance; William K Scott

doi:10.1002/alz.12686

Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets

Alzheimers Dement. 2023 Feb;19(2):611-620. doi: 10.1002/alz.12686. Epub 2022 May 1.

Authors

Jairo Ramos¹, Laura J Caywood¹, Michael B Prough¹, Jason E Clouse¹, Sharlene D Herington¹, Susan H Slifer¹, M Denise Fuzzell², Sarada L Fuzzell², Sherri D Hochstetler², Kristy L Miskimen², Leighanne R Main², Michael D Osterman^{2

3}, Andrew F Zaman¹, Patrice L Whitehead¹, Larry D Adams¹, Renee A Laux², Yeunjoo E Song², Tatiana M Foroud⁴, Richard P Mayeux^{5

6

7}, Peter St George-Hyslop⁸, Paula K Ogrocki⁹, Alan J Lerner⁹, Jeffery M Vance^{1

10}, Michael L Cuccaro^{1

10}, Jonathan L Haines^{2

3}, Margaret A Pericak-Vance^{1

10}, William K Scott^{1

10}

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami Miller School, of Medicine, Miami, Florida, USA.
² Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
³ Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA.
⁴ Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, USA.
⁶ Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.
⁷ Department of Neurology, Columbia University, New York, New York, USA.
⁸ University of Toronto, Toronto, Ontario, Canada.
⁹ University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁰ The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.

Abstract

Introduction: 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.

Keywords: SHISA6 gene; Alzheimer's disease; Cox mixed-effects models; age at onset; cognitive impairment; genome-wide association study; protective variants.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Cognitive Dysfunction* / genetics
Genome-Wide Association Study
Genotype
Humans
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

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