Posts Tagged ‘human variation’

Most significant article published in the Society of Evolution, Medicine and Public Health won Prize: polygenic scores, polygenic adaptation, and human phenotypic differences

Reporter: Aviva Lev-Ari, PhD, RN 


UPDATED on 8/30/2020

Analysis of polygenic risk score usage and performance in diverse human populations


A historical tendency to use European ancestry samples hinders medical genetics research, including the use of polygenic scores, which are individual-level metrics of genetic risk. We analyze the first decade of polygenic scoring studies (2008–2017, inclusive), and find that 67% of studies included exclusively European ancestry participants and another 19% included only East Asian ancestry participants. Only 3.8% of studies were among cohorts of African, Hispanic, or Indigenous peoples. We find that predictive performance of European ancestry-derived polygenic scores is lower in non-European ancestry samples (e.g. African ancestry samples: t = −5.97, df = 24, p = 3.7 × 10−6), and we demonstrate the effects of methodological choices in polygenic score distributions for worldwide populations. These findings highlight the need for improved treatment of linkage disequilibrium and variant frequencies when applying polygenic scoring to cohorts of non-European ancestry, and bolster the rationale for large-scale GWAS in diverse human populations.



The Voice of Prof. Marcus W. Feldman

You might be interested in the paper “interpreting polygenic scores, polygenic adaptation, and human phenotypic differences” by N. Rosenberg, M. Edge, J. Pritchard, and M. Feldman, published in Evolution, Medicine and Public Health  (2019).    Rosenberg and Pritchard are my former PhD students, both full professors at Stanford, and M.Edge is a student of Rosenberg.


On Aug 28, 2020, at 4:36 PM, Horowitz, Barbara Natterson <natterson-horowitz@fas.harvard.edu> wrote:

Dear Dr. Rosenberg,

It is my pleasure in my role as President of the International Society for Evolution, Medicine and Public Health to inform you that your 2019 EMPH article, “Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences” has won The George C. Williams Prize which is awarded each year to the first author of the most significant article published in the Society’s flagship journal, Evolution, Medicine and Public Health.  

The Prize recognizes the contributions of George C. Williams to evolutionary medicine and aims to encourage and highlight important research in this growing field. It includes $5,000 and an invitation to present at the online lecture series, Club EvMed. The Prize is made possible by donations from Doris Williams, Randolph Nesse, and other supporters of EMPH.

The winning article:


Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences

Evolution, Medicine, and Public Health, Volume 2019, Issue 1, 2019, Pages 26–34, https://doi.org/10.1093/emph/eoy036
27 December 2018

Article history



Recent analyses of polygenic scores have opened new discussions concerning the genetic basis and evolutionary significance of differences among populations in distributions of phenotypes. Here, we highlight limitations in research on polygenic scores, polygenic adaptation and population differences. We show how genetic contributions to traits, as estimated by polygenic scores, combine with environmental contributions so that differences among populations in trait distributions need not reflect corresponding differences in genetic propensity. Under a null model in which phenotypes are selectively neutral, genetic propensity differences contributing to phenotypic differences among populations are predicted to be small. We illustrate this null hypothesis in relation to health disparities between African Americans and European Americans, discussing alternative hypotheses with selective and environmental effects. Close attention to the limitations of research on polygenic phenomena is important for the interpretation of their relationship to human population differences.


We are currently witnessing a surge in public interest in the intersection of evolutionary genetics with such topics as cognitive phenotypes, disease, race and heritability of human traits [1–7]. This attention emerges partly from recent advances in genomics, including the introduction of polygenic scores—the aggregation of estimated effects of genome-wide variants to predict the contribution of a person’s genome to a phenotypic trait [8–10]—and a new focus on polygenic adaptations, namely adaptations that have occurred by natural selection on traits influenced by many genes [11–13].

Theories involving natural selection have long been applied in the scientific literature to explain mean phenotypic differences among human populations [14–16]. Although new tools for statistical analysis of polygenic variation and polygenic adaptation provide opportunities for studying human evolution and the genetic basis of traits, they also generate potential for misinterpretation. In the past, public attention to research on human variation and its possible evolutionary basis has often been accompanied by claims that are not justified by the research findings [17]. Recognizing pitfalls in the interpretation of new research on human variation is therefore important for advancing discussions on associated sensitive and controversial topics.

The contribution of polygenic score distributions to phenotype distributions. Two populations are considered, populations 1 (red) and 2 (blue). Each population has a distribution of genetic propensities, which are treated as accurately estimated in the form of polygenic scores (left). The genetic propensity distribution and an environment distribution sum to produce a phenotype distribution (right). All plots have the same numerical scale. (A) Environmental differences amplify an underlying difference in genetic propensities. (B) Populations differ in their phenotypes despite having no differences in genetic propensity distributions. (C) Environmental differences obscure a difference in genetic propensities opposite in direction to the difference in phenotype means. (D) Similarity in phenotype distributions is achieved despite a difference in genetic propensity distributions by an intervention that reduces the environmental contribution for individuals with polygenic scores above a threshold. (E) Within populations, heritability is high, so that genetic variation explains the majority of phenotypic variation; however, the difference between populations is explained by an environmental difference. Panels (A–C and E) present independent normal distributions for genotype and environment that sum to produce normal distributions for phenotype. In (D), (genotype, environment) pairs are simulated from independent normal distributions and a negative constant—reflecting the effect of a medication or other intervention—is added to environmental contributions associated with simulated genotypic values that exceed a threshold


These limitations illustrate that much of the complexity embedded in use of polygenic scores—the effects of the environment on phenotype and its relationship to genotype, the proportion of variance explained, and the peculiarities of the underlying GWAS data that have been used to estimate effect sizes—is obscured by the apparent simplicity of the single values computed for each individual for each phenotype. Consequently, in using polygenic scores to describe genomic contributions to traits, particularly traits for which the total contribution of genetic variation to trait variation, as measured by heritability, is low—but even if it is high (Fig. 1E)—a difference in polygenic scores between populations provides little information about potential genetic bases for trait differences between those populations.

Unlike heritability, which ranges from 0 to 1 and therefore makes it obvious that the remaining contribution to phenotypic variation is summarized by its difference from 1, the limited explanatory role of genetics is not embedded in the nature of the polygenic scores themselves. Although polygenic scores encode knowledge about specific genetic correlates of trait variation, they do not change the conceptual framework for genetic and environmental contribution to population differences. Attributions of phenotypic differences among populations to genetic differences should therefore be treated with as much caution as similar genetic attributions from heritability in the pre-genomic era.


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