Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.
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ABSTRACT:
SUBMITTER: Edwards JJ
PROVIDER: S-EPMC7188873 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
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Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.
Edwards Jonathan J JJ Rouillard Andrew D AD Fernandez Nicolas F NF Wang Zichen Z Lachmann Alexander A Shankaran Sunita S SS Bisgrove Brent W BW Demarest Bradley B Turan Nahid N Srivastava Deepak D Bernstein Daniel D Deanfield John J Giardini Alessandro A Porter George G Kim Richard R Roberts Amy E AE Newburger Jane W JW Goldmuntz Elizabeth E Brueckner Martina M Lifton Richard P RP Seidman Christine E CE Chung Wendy K WK Tristani-Firouzi Martin M Yost H Joseph HJ Ma'ayan Avi A Gelb Bruce D BD
JACC. Basic to translational science 20200408 4
Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 comp ...[more]
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Project description:BackgroundCongenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database.ResultsWe discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327.ConclusionsOur results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.
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