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
{"title":"在中西部阿米什人中,创始人群体特异性权重可提高阿尔茨海默病多基因风险评分的表现。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/20/24/main.PMC10565871.pdf","citationCount":"0","resultStr":"{\"title\":\"Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":34530,\"journal\":{\"name\":\"HGG Advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2023-10-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/20/24/main.PMC10565871.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"HGG Advances\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xhgg.2023.100241\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/9/22 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"HGG Advances","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xhgg.2023.100241","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/9/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.
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.