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Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability.

ABSTRACT: Regulatory variation plays a major role in complex disease and that cell type-specific binding of transcription factors (TF) is critical to gene regulation. However, assessing the contribution of genetic variation in TF-binding sites to disease heritability is challenging, as binding is often cell type-specific and annotations from directly measured TF binding are not currently available for most cell type-TF pairs. We investigate approaches to annotate TF binding, including directly measured chromatin data and sequence-based predictions. We find that TF-binding annotations constructed by intersecting sequence-based TF-binding predictions with cell type-specific chromatin data explain a large fraction of heritability across a broad set of diseases and corresponding cell types; this strategy of constructing annotations addresses both the limitation that identical sequences may be bound or unbound depending on surrounding chromatin context and the limitation that sequence-based predictions are generally not cell type-specific. We partitioned the heritability of 49 diseases and complex traits using stratified linkage disequilibrium (LD) score regression with the baseline-LD model (which is not cell type-specific) plus the new annotations. We determined that 100 bp windows around MotifMap sequenced-based TF-binding predictions intersected with a union of six cell type-specific chromatin marks (imputed using ChromImpute) performed best, with an 58% increase in heritability enrichment compared to the chromatin marks alone (11.6× vs. 7.3×, P = 9 × 10-14 for difference) and a 20% increase in cell type-specific signal conditional on annotations from the baseline-LD model (P = 8 × 10-11 for difference). Our results show that TF-binding annotations explain substantial disease heritability and can help refine genome-wide association signals.

SUBMITTER: van de Geijn B

PROVIDER: S-EPMC7206853 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability.

van de Geijn Bryce B Finucane Hilary H Gazal Steven S Hormozdiari Farhad F Amariuta Tiffany T Liu Xuanyao X Gusev Alexander A Loh Po-Ru PR Reshef Yakir Y Kichaev Gleb G Raychauduri Soumya S Price Alkes L AL

Human molecular genetics 20200501 7

Regulatory variation plays a major role in complex disease and that cell type-specific binding of transcription factors (TF) is critical to gene regulation. However, assessing the contribution of genetic variation in TF-binding sites to disease heritability is challenging, as binding is often cell type-specific and annotations from directly measured TF binding are not currently available for most cell type-TF pairs. We investigate approaches to annotate TF binding, including directly measured ch ...[more]

PMID: 31595288

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Project description:Background"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. adiponectin) is high or low relative to its distribution. We have previously shown that the heritability (h2 ) of adiposity, lipoproteins, postprandial lipemia, pulmonary function, and coffee and alcohol consumption are quantile-specific. Whether adiponectin heritability is quantile specific remains to be determined.MethodsPlasma adiponectin concentrations from 4,182 offspring-parent pairs and 1,662 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (β OP,h2 = 2β OP/(1 + rspouse)) and full-sib regression slopes (β FS, h2 = {(1 + 8rspouse β FS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples.ResultsQuantile-specific h2 (± SE) increased with increasing percentiles of the offspring's age- and sex-adjusted adiponectin distribution when estimated from β OP (P trend = 2.2 × 10-6): 0.30 ± 0.03 at the 10th, 0.33 ± 0.04 at the 25th, 0.43 ± 0.04 at the 50th, 0.55 ± 0.05 at the 75th, and 0.57 ± 0.08 at the 90th percentile, and when estimated from β FS (P trend = 7.6 × 10-7): 0.42 ± 0.03 at the 10th, 0.44 ± 0.04 at the 25th, 0.56 ± 0.05 at the 50th, 0.73 ± 0.08 at the 75th, and 0.79 ± 0.11 at the 90th percentile. Consistent with quantile-dependent expressivity, adiponectin's: (1) heritability was greater in women in accordance with their higher adiponection concentrations; (2) relationships to ADIPOQ polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T> G ADIPOQ polymorphism; (4) difference by ADIPOQ haplotypes increased linearly with increasing postprandial adiponectin concentrations.ConclusionAdiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.

Dataset Information

Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability.

Publications

Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability.

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