Background: Insulin resistance (IR) is a major risk factor for Alzheimer’s Disease (AD) and has been associated with cognitive impairment, dementia, and neurodegeneration. Though the association between IR and AD has been explored genetically, the proportion of variance explained (PVE) by the IR genetic instruments has been limited, due to few genetic loci identified in genome-wide association studies (GWAS) of IR.
Methods: We constructed polygenic scores (PSs) for fasting insulin (FI) based on the Trans-Omics for Precision Medicine (TOPMed) Freeze 9 whole-genome sequencing (WGS) data. We used PRS-CSx (Ruan et al., Nat Genet. 2022) to generate ancestry-specific PSs (European, African, and Hispanic/Latino), with weights derived based on ancestry-specific UK Biobank reference panels and FI GWAS summary statistics adjusted for body mass index (BMI) (Chen et al., Nat Genet., 2021). We used MetaSubtract (Nolte et al., Eur J Hum Genet. 2017) to remove the effect of TOPMed studies from the FI meta-analyses. We generated a multi-ancestry PSFI by fitting a linear combination of the standardized ancestry-specific PSs that most accurately predicted HOMA-IR in five TOPMed cohorts (validation set, N~17k participants [34% European, 28% African, 38% Hispanic] without diabetes), adjusting for BMI. We then evaluated the association of the multi-ancestry PSFI with HOMA-IR, AD, dementia, general cognitive function, and four brain volumes in eight TOPMed cohorts (testing set, ~14k participants [66% European, 22% African, 11% Hispanic]). Association analyses were performed using logistic or linear mixed-effect models adjusted for age, sex, study, 11 genetic principal components, and accounting for relatedness using a genetic relationship matrix. General cognitive function and brain volumes analyses were additionally adjusted for education and intracranial volume (ICV) respectively. We used a threshold of P<0.05/Ntraits/Ntests=0.05/7/4=0.002 to define an association as significant.
Results: The multi-ancestry PSFI was strongly associated with HOMA-IR (PVEJoint=12%). No significant or suggestive association was detected for the multi-ancestry, the African, or the Hispanic PSFI with any of the neurological outcomes. The European PSFI was significantly associated with ICV (P=7E-07), and suggestively associated with lateral ventricular (P=0.004) and total brain volumes (P=0.05).
Conclusion: By leveraging multi-ancestry and WGS data, we increased the PVE of the genetic instruments for IR and confirmed the association of IR with brain volumes. The identified European-specific associations require further investigation.
Funding: NIH K99AG066849-02