Phenome-Wide Association Study of Polygenic Risk Score for Alzheimer’s Disease in Electronic Health Records

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and a growing public health burden in the United States. Significant progress has been made in identifying genetic risk for AD, but limited studies have investigated how AD genetic risk may be associated with other disease conditions in an unbiased fashion. In this study, we conducted a phenome-wide association study (PheWAS) by genetic ancestry groups within a large academic health system using the polygenic risk score (PRS) for AD. PRS was calculated using LDpred2 with genome-wide association study (GWAS) summary statistics. Phenotypes were extracted from electronic health record (EHR) diagnosis codes and mapped to more clinically meaningful phecodes. Logistic regression with Firth’s bias correction was used for PRS phenotype analyses. Mendelian randomization was used to examine causality in significant PheWAS associations. Our results showed a strong association between AD PRS and AD phenotype in European ancestry (OR = 1.26, 95% CI: 1.13, 1.40). Among a total of 1,515 PheWAS tests within the European sample, we observed strong associations of AD PRS with AD and related phenotypes, which include mild cognitive impairment (MCI), memory loss, and dementias. We observed a phenome-wide significant association between AD PRS and gouty arthropathy (OR = 0.90, adjusted p = 0.05). Further causal inference tests with Mendelian randomization showed that gout was not causally associated with AD. We concluded that genetic predisposition of AD was negatively associated with gout, but gout was not a causal risk factor for AD. Our study evaluated AD PRS in a real-world EHR setting and provided evidence that AD PRS may help to identify individuals who are genetically at risk of AD and other related phenotypes. We identified non-neurodegenerative diseases associated with AD PRS, which is essential to understand the genetic architecture of AD and potential side effects of drugs targeting genetic risk factors of AD. Together, these findings expand our understanding of AD genetic and clinical risk factors, which provide a framework for continued research in aging with the growing number of real-world EHR linked with genetic data.

Improving genetic risk modeling of dementia from real-world data in underrepresented populations

“…Polygenic risk scores (PRSs), which aggregate the effects of many genetic variants associated with a disease, have recently been used to quantify an individual's genetic predisposition for complex diseases like dementia. 9 A growing number of studies have underscored the robust links between AD PRS and AD phenotype, [10][11][12][13] declines in memory and executive function, [14][15][16][17] clinical progression, 15 and amyloid load 18 in the non-Hispanic white population. However, the performance of PRSs in non-European ancestries has been suboptimal.…”

“…Compared to traditional cohorts, EHR cohorts offer additional benefits, such as vast sample sizes, diverse phenotypes, and a more inclusive representation of often underrepresented groups, like minorities and older adults. 28 However, only a few genetic studies on dementia have been conducted within the context of EHR, and have predominantly focus on AD 11,29…”

Improving genetic risk modeling of dementia from real-world data in underrepresented populations

“…Polygenic risk scores (PRSs), which aggregate the effects of many genetic variants associated with a disease, have recently been used to quantify an individual's genetic predisposition for complex diseases like dementia. 9 A growing number of studies have underscored the robust links between AD PRS and AD phenotype, [10][11][12][13] declines in memory and executive function, [14][15][16][17] clinical progression, 15 and amyloid load 18 in the non-Hispanic white population. However, the performance of PRSs in non-European ancestries has been suboptimal.…”

Discovery of Drug-Responsive Phenomic Alteration-Related Driver Genes in the Treatment of Coronary Heart Disease

“… 24 It has also been used to assess the polygenic risk score for Alzheimer’s disease in electronic health records. 25 Nevertheless, studies on the genetic associations in drug-responsive phenome alterations are rare. Moreover, there is little information on which genes drive the dynamic genetic variations and the associations among the XYZ phenome and its component symptoms.…”