Identification of a pleiotropic effect of ADIPOQ on cardiac dysfunction and Alzheimer’s disease based on genetic evidence and health care records

Abstract

Observations of comorbidity in heart diseases, including cardiac dysfunction (CD) are increasing, including and cognitive impairment, such as Alzheimer’s disease and dementia (AD/D). This comorbidity might be due to a pleiotropic effect of genetic variants shared between CD and AD/D. Here, we validated comorbidity of CD and AD/D based on diagnostic records from millions of patients in Korea and the University of California, San Francisco Medical Center (odds ratio 11.5 [8.5–15.5, 95% Confidence Interval (CI)]). By integrating a comprehensive human disease–SNP association database (VARIMED, VARiants Informing MEDicine) and whole-exome sequencing of 50 brains from individuals with and without Alzheimer's disease (AD), we identified missense variants in coding regions including APOB , a known risk factor for CD and AD/D, which potentially have a pleiotropic role in both diseases. Of the identified variants, site-directed mutation of ADIPOQ (268 G > A; Gly90Ser) in neurons produced abnormal aggregation of tau proteins ( p = 0.02), suggesting a functional impact for AD/D. The association of CD and ADIPOQ variants was confirmed based on domain deletion in cardiac cells. Using the UK Biobank including data from over 500000 individuals, we examined a pleiotropic effect of the ADIPOQ variant by comparing CD- and AD/D-associated phenotypic evidence, including cardiac hypertrophy and cognitive degeneration. These results indicate that convergence of health care records and genetic evidences may help to dissect the molecular underpinnings of heart disease and associated cognitive impairment, and could potentially serve a prognostic function. Validation of disease–disease associations through health care records and genomic evidence can determine whether health conditions share risk factors based on pleiotropy.

Adiponectin Gene Polymorphisms: A Case–Control Study on Their Role in Late-Onset Alzheimer’s Disease Risk

“…Others, such as rs185847354 (Ile164Thr) and rs121917815 (Arg112Cys), disrupt the assembly into low-molecular-weight trimers [ 33 , 47 , 48 , 62 , 74 , 110 , 111 , 112 , 113 , 114 ]. Interestingly, the rs62625753 (c.268G>A; Gly90Ser) mutation in exon 3 was recently shown to produce abnormal aggregation of tau proteins and contribute to cognitive degeneration, suggesting a functional impact for AD [ 115 ]. Hence, large-scale studies focusing on low-frequency and rare exon variants may have the potential to identify causal ADIPOQ mutations with larger pathogenic effects in a small subset of AD patients, eventually helping to explain a portion of the so-called missing heritability.…”

Cross-phenotype associations between Alzheimer’s Disease and its comorbidities may provide clues to progression

“…In addition to T2D, cardiovascular disease, gastrointestinal (GI) dysfunction, and depression have all been associated with AD, often occurring well before an AD diagnosis [15][16][17][18][19][20][21] . Several known AD risk variants have been identified as pleiotropic between AD and other disorders 8,22,23 . All of these comorbidities suggest that broadly exploring pleiotropy between AD-associated variants/genes and other clinical phenotypes may lead to potential avenues for future therapeutic opportunities.…”