Polygenic scoring accuracy varies across the genetic ancestry continuum. 2023

Yi Ding, and Kangcheng Hou, and Ziqi Xu, and Aditya Pimplaskar, and Ella Petter, and Kristin Boulier, and Florian Privé, and Bjarni J Vilhjálmsson, and Loes M Olde Loohuis, and Bogdan Pasaniuc
Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA. yiding920@ucla.edu.

Polygenic scores (PGSs) have limited portability across different groupings of individuals (for example, by genetic ancestries and/or social determinants of health), preventing their equitable use1-3. PGS portability has typically been assessed using a single aggregate population-level statistic (for example, R2)4, ignoring inter-individual variation within the population. Here, using a large and diverse Los Angeles biobank5 (ATLAS, n = 36,778) along with the UK Biobank6 (UKBB, n = 487,409), we show that PGS accuracy decreases individual-to-individual along the continuum of genetic ancestries7 in all considered populations, even within traditionally labelled 'homogeneous' genetic ancestries. The decreasing trend is well captured by a continuous measure of genetic distance (GD) from the PGS training data: Pearson correlation of -0.95 between GD and PGS accuracy averaged across 84 traits. When applying PGS models trained on individuals labelled as white British in the UKBB to individuals with European ancestries in ATLAS, individuals in the furthest GD decile have 14% lower accuracy relative to the closest decile; notably, the closest GD decile of individuals with Hispanic Latino American ancestries show similar PGS performance to the furthest GD decile of individuals with European ancestries. GD is significantly correlated with PGS estimates themselves for 82 of 84 traits, further emphasizing the importance of incorporating the continuum of genetic ancestries in PGS interpretation. Our results highlight the need to move away from discrete genetic ancestry clusters towards the continuum of genetic ancestries when considering PGSs.

UI MeSH Term Description Entries
D005060 Europe The continent north of AFRICA, west of ASIA and east of the ATLANTIC OCEAN. Northern Europe,Southern Europe,Western Europe
D006113 United Kingdom Country in northwestern Europe including Great Britain and the northern one-sixth of the island of Ireland, located between the North Sea and north Atlantic Ocean. The capital is London. Great Britain,Isle of Man
D006630 Hispanic or Latino A person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race (https://www.federalregister.gov/documents/1997/10/30/97-28653/revisions-to-the-standards-for-the-classification-of-federal-data-on-race-and-ethnicity). In the United States it is used for classification of federal government data on race and ethnicity. Race and ethnicity terms are self-identified social construct and may include terms outdated and offensive in MeSH to assist users who are interested in retrieving comprehensive search results for studies such as in longitudinal studies. Cuban Americans,Hispanic Americans,Latin Americans, US,Latinas,Latinos,Latinx,Puerto Ricans,Spanish Americans,Hispanics,American, Hispanic,American, US Latin,Cuban American,Hispanic American,Hispanic or Latinos,Latin American, US,Latina,Latino,Puerto Rican,Spanish American,US Latin American,US Latin Americans
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000094854 European People People native to or inhabitants of EUROPE. European Person,Europeans,European Peoples,European Persons,People, European,Person, European,Persons, European
D015141 Los Angeles City in California.
D044465 White People Persons having origins in any of the white racial groups of Europe, the Middle East, or North Africa. Note that OMB category WHITE is available for the United States population groups. Race and ethnicity terms, as used in the federal government, are self-identified social construct and may include terms outdated and offensive in MeSH to assist users who are interested in retrieving comprehensive search results for studies such as in longitudinal studies. European Continental Ancestry Group,White Person,Caucasian Race,Caucasoid Race,Caucasian Races,Caucasoid Races,People, White,Person, White,Race, Caucasian,Race, Caucasoid,White Peoples,White Persons
D044469 Racial Groups Groups of individuals with similar physical appearances often reinforced by cultural, social and/or linguistic similarities. Continental Population Groups,Race,Racial Stocks,Continental Population Group,Group, Continental Population,Group, Racial,Groups, Continental Population,Groups, Racial,Population Group, Continental,Population Groups, Continental,Races,Racial Group,Racial Stock,Stock, Racial,Stocks, Racial
D020412 Multifactorial Inheritance A pattern of inheritance of a trait that includes the contributions from more than one gene. Oligogenic Inheritance,Polygenic Inheritance,Polygenic Traits,Complex Inheritance,Complex Traits,Multigenic Inheritance,Multigenic Traits,Oligogenic Traits,Polygenic Characters,Character, Polygenic,Characters, Polygenic,Complex Trait,Inheritance, Complex,Inheritance, Multifactorial,Inheritance, Multigenic,Inheritance, Oligogenic,Inheritance, Polygenic,Multigenic Trait,Oligogenic Trait,Polygenic Character,Polygenic Trait,Trait, Complex,Trait, Multigenic,Trait, Oligogenic,Trait, Polygenic,Traits, Complex,Traits, Multigenic,Traits, Oligogenic,Traits, Polygenic
D030541 Databases, Genetic Databases devoted to knowledge about specific genes and gene products. Genetic Databases,Genetic Sequence Databases,OMIM,Online Mendelian Inheritance In Man,Genetic Data Banks,Genetic Data Bases,Genetic Databanks,Genetic Information Databases,Bank, Genetic Data,Banks, Genetic Data,Data Bank, Genetic,Data Banks, Genetic,Data Base, Genetic,Data Bases, Genetic,Databank, Genetic,Databanks, Genetic,Database, Genetic,Database, Genetic Information,Database, Genetic Sequence,Databases, Genetic Information,Databases, Genetic Sequence,Genetic Data Bank,Genetic Data Base,Genetic Databank,Genetic Database,Genetic Information Database,Genetic Sequence Database,Information Database, Genetic,Information Databases, Genetic,Sequence Database, Genetic,Sequence Databases, Genetic

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