ORCID Profile
0000-0002-1486-7495
Current Organisations
Harvard Medical School
,
Brigham and Women's Hospital
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Publisher: Public Library of Science (PLoS)
Date: 27-12-2022
DOI: 10.1371/JOURNAL.PGEN.1010557
Abstract: Genetic association studies of many heritable traits resulting from physiological testing often have modest s le sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of erse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For ex le, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 ( PRIM1 ) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV 1 /FVC), and an eQTL of matrix metallopeptidase 15 ( MMP15 ) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 ( HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble erse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/652966
Abstract: Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 in iduals of erse ancestry and 4 replicated common variant associations with inclusion of additional s les (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 −8 ) on chromosome X with ARMCX3 . Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A -mediated hypoxic response.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
Publisher: American Thoracic Society
Date: 15-11-2022
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
No related grants have been discovered for Heming Wang.