Functional Architecture of Low-frequency Variants Highlights Strength of Negative Selection Across Coding and Non-coding Annotations

Overview

Journal Nat Genet

Specialty Genetics

Date 2018 Oct 10

PMID 30297966

Citations 89

Authors

Steven Gazal

Po-Ru Loh

Hilary K Finucane

Andrea Ganna

Armin Schoech

Shamil Sunyaev

Alkes L Price

Affiliations

Soon will be listed here.

Abstract

Common variant heritability has been widely reported to be concentrated in variants within cell-type-specific non-coding functional annotations, but little is known about low-frequency variant functional architectures. We partitioned the heritability of both low-frequency (0.5%≤ minor allele frequency <5%) and common (minor allele frequency ≥5%) variants in 40 UK Biobank traits across a broad set of functional annotations. We determined that non-synonymous coding variants explain 17 ± 1% of low-frequency variant heritability ([Formula: see text]) versus 2.1 ± 0.2% of common variant heritability ([Formula: see text]). Cell-type-specific non-coding annotations that were significantly enriched for [Formula: see text] of corresponding traits were similarly enriched for [Formula: see text] for most traits, but more enriched for brain-related annotations and traits. For example, H3K4me3 marks in brain dorsolateral prefrontal cortex explain 57 ± 12% of [Formula: see text] versus 12 ± 2% of [Formula: see text] for neuroticism. Forward simulations confirmed that low-frequency variant enrichment depends on the mean selection coefficient of causal variants in the annotation, and can be used to predict effect size variance of causal rare variants (minor allele frequency <0.5%).

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References

Mancuso N, Rohland N, Rand K, Tandon A, Allen A, Quinque D . The contribution of rare variation to prostate cancer heritability. Nat Genet. 2015; 48(1):30-5. PMC: 7534691. DOI: 10.1038/ng.3446. View

Short P, McRae J, Gallone G, Sifrim A, Won H, Geschwind D . De novo mutations in regulatory elements in neurodevelopmental disorders. Nature. 2018; 555(7698):611-616. PMC: 5912909. DOI: 10.1038/nature25983. View

Finucane H, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P . Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015; 47(11):1228-35. PMC: 4626285. DOI: 10.1038/ng.3404. View

Tennessen J, Bigham A, OConnor T, Fu W, Kenny E, Gravel S . Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012; 337(6090):64-9. PMC: 3708544. DOI: 10.1126/science.1219240. View

Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker S, Erdos M . Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature. 2015; 520(7548):558-62. PMC: 4409450. DOI: 10.1038/nature14154. View

Yang J, Bakshi A, Zhu Z, Hemani G, Vinkhuyzen A, Lee S . Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat Genet. 2015; 47(10):1114-20. PMC: 4589513. DOI: 10.1038/ng.3390. View

Marouli E, Graff M, Medina-Gomez C, Lo K, Wood A, Kjaer T . Rare and low-frequency coding variants alter human adult height. Nature. 2017; 542(7640):186-190. PMC: 5302847. DOI: 10.1038/nature21039. View

Loh P, Tucker G, Bulik-Sullivan B, Vilhjalmsson B, Finucane H, Salem R . Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015; 47(3):284-90. PMC: 4342297. DOI: 10.1038/ng.3190. View

Ionita-Laza I, McCallum K, Xu B, Buxbaum J . A spectral approach integrating functional genomic annotations for coding and noncoding variants. Nat Genet. 2016; 48(2):214-20. PMC: 4731313. DOI: 10.1038/ng.3477. View

10.

Davydov E, Goode D, Sirota M, Cooper G, Sidow A, Batzoglou S . Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010; 6(12):e1001025. PMC: 2996323. DOI: 10.1371/journal.pcbi.1001025. View

11.

Zuk O, Schaffner S, Samocha K, Do R, Hechter E, Kathiresan S . Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci U S A. 2014; 111(4):E455-64. PMC: 3910587. DOI: 10.1073/pnas.1322563111. View

12.

Simons Y, Bullaughey K, Hudson R, Sella G . A population genetic interpretation of GWAS findings for human quantitative traits. PLoS Biol. 2018; 16(3):e2002985. PMC: 5871013. DOI: 10.1371/journal.pbio.2002985. View

13.

Leslie S, Winney B, Hellenthal G, Davison D, Boumertit A, Day T . The fine-scale genetic structure of the British population. Nature. 2015; 519(7543):309-314. PMC: 4632200. DOI: 10.1038/nature14230. View

14.

Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H . Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet. 2010; 42(11):969-72. DOI: 10.1038/ng.680. View

15.

Walter K, Min J, Huang J, Crooks L, Memari Y, McCarthy S . The UK10K project identifies rare variants in health and disease. Nature. 2015; 526(7571):82-90. PMC: 4773891. DOI: 10.1038/nature14962. View

16.

Ritchie G, Dunham I, Zeggini E, Flicek P . Functional annotation of noncoding sequence variants. Nat Methods. 2014; 11(3):294-6. PMC: 5015703. DOI: 10.1038/nmeth.2832. View

17.

Fuchsberger C, Flannick J, Teslovich T, Mahajan A, Agarwala V, Gaulton K . The genetic architecture of type 2 diabetes. Nature. 2016; 536(7614):41-47. PMC: 5034897. DOI: 10.1038/nature18642. View

18.

Siepel A, Bejerano G, Pedersen J, Hinrichs A, Hou M, Rosenbloom K . Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005; 15(8):1034-50. PMC: 1182216. DOI: 10.1101/gr.3715005. View

19.

Bulik-Sullivan B, Loh P, Finucane H, Ripke S, Yang J, Patterson N . LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015; 47(3):291-5. PMC: 4495769. DOI: 10.1038/ng.3211. View

20.

Loh P, Kichaev G, Gazal S, Schoech A, Price A . Mixed-model association for biobank-scale datasets. Nat Genet. 2018; 50(7):906-908. PMC: 6309610. DOI: 10.1038/s41588-018-0144-6. View