Sex differences in the genetic predictors of Alzheimer’s pathology

Alzheimer’s Disease Genetics Consortium, Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

Abstract

Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

Original languageEnglish (US)
Pages (from-to)2581-2589
Number of pages9
JournalBrain
Volume142
Issue number9
DOIs
StatePublished - Sep 1 2019

Fingerprint

Sex Characteristics
Pathology
Genome-Wide Association Study
Endophenotypes
Alzheimer Disease
Age of Onset
Autopsy
Neurofibrillary Tangles
Chromosomes, Human, Pair 7
Executive Function
Neuroimaging
Genome
Databases
Brain
Datasets

Keywords

  • Alzheimer’s disease
  • Beta-amyloid
  • Genome-wide association study
  • Neuropathology
  • Tau

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Alzheimer’s Disease Genetics Consortium, & Alzheimer’s Disease Neuroimaging Initiative (2019). Sex differences in the genetic predictors of Alzheimer’s pathology. Brain, 142(9), 2581-2589. https://doi.org/10.1093/brain/awz206

Sex differences in the genetic predictors of Alzheimer’s pathology. / Alzheimer’s Disease Genetics Consortium; Alzheimer’s Disease Neuroimaging Initiative.

In: Brain, Vol. 142, No. 9, 01.09.2019, p. 2581-2589.

Research output: Contribution to journalArticle

Alzheimer’s Disease Genetics Consortium & Alzheimer’s Disease Neuroimaging Initiative 2019, 'Sex differences in the genetic predictors of Alzheimer’s pathology', Brain, vol. 142, no. 9, pp. 2581-2589. https://doi.org/10.1093/brain/awz206
Alzheimer’s Disease Genetics Consortium, Alzheimer’s Disease Neuroimaging Initiative. Sex differences in the genetic predictors of Alzheimer’s pathology. Brain. 2019 Sep 1;142(9):2581-2589. https://doi.org/10.1093/brain/awz206
Alzheimer’s Disease Genetics Consortium ; Alzheimer’s Disease Neuroimaging Initiative. / Sex differences in the genetic predictors of Alzheimer’s pathology. In: Brain. 2019 ; Vol. 142, No. 9. pp. 2581-2589.
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abstract = "Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70{\%}). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.",
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