Variance quantitative trait locus-guided gene–environment interaction analysis of all-cause dementia, Alzheimer’s disease and vascular dementia.   — The Association Specialists
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Variance quantitative trait locus-guided gene–environment interaction analysis of all-cause dementia, Alzheimer’s disease and vascular dementia.   (24222)

Anwar Mulugeta Gebremichael 1 2 3 , Beben Benyamin 1 2 , S. Hong Lee 1 2 , Elina Hypponen-Hedger 1 2
  1. Australian Centre for Precision Health, School of Public Health , Adelaide, South Australia, Australia
  2. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  3. Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia

Background: Dementia is a progressive, irreversible syndrome characterised by cognitive decline, arising from interactions by genetic and environmental factors. Using a variance quantitative trait locus (vQTL)–guided gene–environment interaction (G×E) framework, we investigated genetic loci showing environment-dependent effects on susceptibility to all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD).

Methods: We analysed data from 304,996 UK biobank participants, including 6,632 all-cause dementia, 2,951 AD, and 1,448 VaD cases. vQTL analyses were conducted using median-based Levene’s test, with sensitivity analyses using the squared residual value linear model and modified Levene’s test.  vQTL signals were subsequently examined for interaction with age, sex, smoking, alcohol consumption, body mass index, physical activity, and serum 25-hydroxyvitamin D. Stratified analyses were undertaken where evidence of interaction was observed.

Results: We identified 24, 83, and 221 independent vQTLs at genome-wide significance for all-cause dementia, AD, and VaD, respectively, with a shared locus in the APOE region across outcomes. From all vQTL signals, 58%, 28%, and 12% replicated across sensitivity analyses for all-cause dementia, AD and VaD, respectively. Follow-on analyses identified 44 interactions at the nominal significance, three of which remained after false discovery rate correction. Stratified analyses confirmed age- and sex-dependent heterogeneity within the APOE region. G×E-informed stratified analyses suggested potentially novel loci for all-cause dementia (n = 1), AD (n = 2), and VaD (n = 4).

Conclusion: Our vQTL-guided GxE framework confirmed known age- and sex-based interactions (e.g., in the APOE region) and identified potential novel loci showing effect heterogeneity depending on the environment.