[RESULTS] Using constraint calculated across placental mammals, 3.3% of bases in the human genome are significantly constrained, including 57.6% of coding bases. Most constrained bases (80.7%) are noncoding. Common variants (allele frequency ≥ 5%) and low-frequency variants (0.5% ≤ allele frequency < 5%) are depleted for constrained bases (1.85 versus 3.26% expected by chance, P < 2.2 × 10−308). Pathogenic ClinVar variants are more constrained than benign variants (P < 2.2 × 10−16). The most constrained common variants are more enriched for disease single-nucleotide polymorphism (SNP)–heritability in 63 independent GWASs. The enrichment of SNP-heritability in constrained regions is greater (7.8-fold) than previously reported in mammals and is even higher in primates (11.1-fold). It exceeds the enrichment of SNP-heritability in nonsynonymous coding variants (7.2-fold) and fine-mapped expression quantitative trait loci (eQTL)–SNPs (4.8-fold). The enrichment peaks near constrained bases, with a log-linear decrease of SNP-heritability enrichment as a function of the distance to a constrained base. Zoonomia constraint scores improve functionally informed fine-mapping. Variants at sites constrained in mammals and primates have greater posterior inclusion probabilities and higher per-SNP contributions. In addition, using both constraint and functional annotations improves polygenic risk score accuracy across a range of traits. Finally, incorporating constraint information into the analysis of noncoding somatic variants in medulloblastomas identifies new candidate driver genes.

This work was funded by the Swedish Research Council and Knut and Alice Wallenberg Foundation, Swedish Cancer Society, Swedish Childhood Cancer Fund, National Institute of Mental Health (NIMH) U01MH116438, Gladstone Institutes, National Institute on Drug Abuse (NIDA) DP1DA04658501, NIDA F30DA053020, University College Dublin (UCD) Ad Astra Fellowship, and National Human Genome Research Institute (NHGRI) R01HG008742 and U41HG002371. S.G. was supported by National Institutes of Health (NIH) grants R00 HG010160 and R35 GM147789. Y.L. was supported by NIH U01 HG011720. Additional support was provided by the Australian National Health and Medical Research Council (1113400, 1173790, and 1177268). L.M.H. was supported by NIH grants MH118278, MH124839, and ES033630. P.F.S. was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501). This study makes use of data from the UK Biobank (project ID 12505).

[RATIONALE] We compared genomes from hundreds of mammals and identified bases with unusually few variants (evolutionarily constrained). Constraint is a measure of functional importance that is agnostic to cell type or developmental stage. It can be applied to investigate any heritable disease or trait and is complementary to resources using cell type– and time point–specific functional assays like Encyclopedia of DNA Elements (ENCODE) and Genotype-Tissue Expression (GTEx).

[INTRODUCTION] Thousands of genetic variants have been associated with human diseases and traits through genome-wide association studies (GWASs). Translating these discoveries into improved therapeutics requires discerning which variants among hundreds of candidates are causally related to disease risk. To date, only a handful of causal variants have been confirmed. Here, we leverage 100 million years of mammalian evolution to address this major challenge.

[CONCLUSION] Genome-wide measures of evolutionary constraint can help discern which variants are functionally important. This information may accelerate the translation of genomic discoveries into the biological, clinical, and therapeutic knowledge that is required to understand and treat human disease.

Peer reviewed