Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish

Michael D Osterman; Yeunjoo E Song; Audrey Lynn; Kristy Miskimen; Larry D Adams; Renee A Laux; Laura J Caywood; Michael B Prough; Jason E Clouse; Sharlene D Herington; Susan H Slifer; Sarada L Fuzzell; Sherri D Hochstetler; Leighanne R Main; Daniel A Dorfsman; Andrew F Zaman; Paula Ogrocki; Alan J Lerner; Jeffery M Vance; Michael L Cuccaro; William K Scott; Margaret A Pericak-Vance; Jonathan L Haines

doi:10.1016/j.xhgg.2023.100241

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish

HGG Adv. 2023 Oct 12;4(4):100241. doi: 10.1016/j.xhgg.2023.100241. Epub 2023 Sep 22.

Authors

Michael D Osterman¹, Yeunjoo E Song², Audrey Lynn², Kristy Miskimen³, Larry D Adams⁴, Renee A Laux³, Laura J Caywood⁴, Michael B Prough⁴, Jason E Clouse⁴, Sharlene D Herington⁴, Susan H Slifer⁴, Sarada L Fuzzell³, Sherri D Hochstetler³, Leighanne R Main⁵, Daniel A Dorfsman⁶, Andrew F Zaman⁴, Paula Ogrocki⁷, Alan J Lerner⁷, Jeffery M Vance⁶, Michael L Cuccaro⁶, William K Scott⁶, Margaret A Pericak-Vance⁶, Jonathan L Haines⁸

Affiliations

¹ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA. Electronic address: mdo17@case.edu.
² Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
³ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
⁴ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁵ Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
⁶ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁷ Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
⁸ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA. Electronic address: jlh213@case.edu.

Abstract

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.

Keywords: APOE; Alzheimer's disease; Amish; cognitive impairment; founder population; genetic risk score; genetics; genome-wide association study; polygenic risk score; populations.

MeSH terms

Alzheimer Disease* / epidemiology
Amish
Genetic Risk Score
Genome-Wide Association Study
Humans
Risk Factors
United States

Abstract

MeSH terms

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