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Cited by 27Genetic Associations and EpidemiologyGenetic and phenotypic traits in livestockGenetic Mapping and Diversity in Plants and Animals

Characterizing the effect of background selection on the polygenicity of brain-related traits

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Wendt, Frank R., Pathak, Gita A., Overstreet, Cassie, Tylee, Daniel S., Gelernter, Joel, Atkinson, Elizabeth G., Polimanti, Renato·2021·Genomics
DOI 10.1016/j.ygeno.2020.11.032PMC PMC7855394
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Abstract

Background Genome-wide association studies (GWAS) have demonstrated that psychopathology phenotypes are affected by many risk alleles with small effect (polygenicity). It is unclear how ubiquitously evolutionary pressures influence the genetic architecture of these traits. Methods We partitioned SNP heritability to assess the contribution of background (BGS) and positive selection, Neanderthal local ancestry, functional significance, and genotype networks in 75 brain-related traits (8411 ≤ N ≤ 1,131,181, mean N = 205,289). We applied binary annotations by dichotomizing each measure based on top 2%, 1%, and 0.5% of all scores genome-wide. Effect size distribution features were calculated using GENESIS. We tested the relationship between effect size distribution descriptive statistics and natural selection. In a subset of traits, we explore the inclusion of diagnostic heterogeneity (e.g., number of diagnostic combinations and total symptoms) in the tested relationship. Results SNP-heritability was enriched (false discovery rate q < 0.05) for loci with elevated BGS (7 phenotypes) and in genic (34 phenotypes) and loss-of-function (LoF)-intolerant regions (67 phenotypes). These effects were strongest in GWAS of schizophrenia (1.90-fold BGS, 1.16-fold genic, and 1.92-fold LoF), educational attainment (1.86-fold BGS, 1.12-fold genic, and 1.79-fold LoF), and cognitive performance (2.29-fold BGS, 1.12-fold genic, and 1.79-fold LoF). BGS (top 2%) significantly predicted effect size variance for trait-associated loci (σ 2 parameter) in 75 brain-related traits (β = 4.39 × 10-5, p = 1.43 × 10-5, model r 2 = 0.548). Considering the number of DSM-5 diagnostic combinations per psychiatric disorder improved model fit (σ 2 ~ B Top2% × Genic × diagnostic combinations; model r 2 = 0.661). Conclusions Brain-related phenotypes with larger variance in risk locus effect sizes are associated with loci under BGS. We show exploratory results suggesting that diagnostic complexity may also contribute to the increased polygenicity of psychiatric disorders.

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  • The strongest enrichments in both ancestry groups were observed for annotations related to genic and LoF intolerant regions.

    “In line with previous studies [10, 33], the strongest enrichments in both ancestry groups were observed for annotations related to genic and LoF intolerant regions.”

    From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [10]

    The Results section (‘Enrichment of Genic and Loss-of-Function Intolerance’; page unavailable) reports significant enrichment for genic and LoF-intolerant loci across many phenotypes. It does not establish that these were the strongest annotations in both ancestry groups. The Datasets section describes a European LD reference panel, not a comparison of enrichment results between two ancestry groups. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Previous studies showed that Neanderthal-introgressed loci are associated with immunological, neurological, psychiatric, metabolic, cardiovascular, and dermatological outcomes in EUR populations.

    “Previous studies showed that Neanderthal-introgressed loci are associated with immunological, neurological, psychiatric, metabolic, cardiovascular, and dermatological outcomes in EUR populations [10, 15–17].”

    From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [10]

    The Results section, “Enrichment of Neanderthal Introgression” (page unavailable), reports a significant relationship between Neanderthal local-ancestry SNPs and heritability of neuroticism, a brain-related trait. It does not report associations across the claimed immunological, metabolic, cardiovascular, or dermatological outcomes; the cited result is a depletion of heritability at high-Neanderthal-ancestry SNPs, not a catalogue of associated loci across those domains. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Positive selection was detected in complex traits previously.

    “Positive selection, a measure for adaptive evolution was also detected in complex traits previously [10–12].”

    From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [10]

  • Functionally important regions of the genome contribute to SNP-h2 to a different extent compared to the other annotations tested.

    “In our evolution-focused SNP-h2 enrichment analysis, we detected an overabundance of genic and LoF intolerant loci in both EAS and EUR, suggesting that functionally important regions of the genome contribute to SNP-h2 to a different extent compared to the other annotations tested [10, 33, 40, 44].”

    From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [10]

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Cited by

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Authors
Wendt, F. R., Pathak, G. A., Overstreet, C., Tylee, D. S., Gelernter, J., Atkinson, E. G., & Polimanti, R.
Affiliations
  • Yale University (US)
  • Broad Institute (US)
Corresponding author
Polimanti, Renato
ORCID
Venue
Genomics
Publisher
Elsevier BV
Published
2021-01
Volume
113
Issue
1
Pages
111-119
ISSN
0888-7543 (ISSN-L)
DOI
10.1016/j.ygeno.2020.11.032
PMC
PMC7855394
OpenAlex
W3109891594
Cited by
27
References
8
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 7
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Genomics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Foundation for Suicide Prevention
  • U.S. Department of Veterans Affairs
  • National Institutes of Health
  • Simons Foundation Autism Research Initiative
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
background selection, polygenicity, SNP heritability, positive selection, loss-of-function intolerance, genotype networks, effect size distribution, schizophrenia, educational attainment, cognitive performance, diagnostic heterogeneity, mental illness, natural selection
MeSH terms
Genetic Background, Mental Disorders, Brain, Humans, Phenotype, Selection, Genetic, Genetic Heterogeneity, Multifactorial Inheritance, Polymorphism, Single Nucleotide

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