Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

Qiao L, Welch CL, Hernan R, Wynn J, Krishnan US, Khlevner J, De A, Farkouh-Karoleski C, Wagner AJ, Heydweiller A, et al, High FA, Sun X, Donahoe PK, Bendixen C, Brosens E, Shen Y [+], Chung WK [+]

AJHG, 2024.

Lab members marked as bold; [+] co-senior authors

Abstract

Background - Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy number variations contribute to CDH. However, the majority of CDH cases remain unexplained.

Methods – We performed integrated de novo and common variant analyses using 1,469 CDH cases, including 1,064 child-parent trios, from the multicenter Diaphragmatic Hernia Research & Exploration; Advancing Molecular Science (DHREAMS) study and Boston cohorts. Sixty-three percent of cases were diagnosed with CDH alone (“isolated”) and 34% with CDH plus other anomalies (“complex:” 54% cardiac defects, 24.7% neuro behavioral conditions, and 5.9% pulmonary defects excluding pulmonary hypoplasia and hypertension). 6,133 ancestry-matched, unaffected parents from the Simons Powering Autism Research for Knowledge (SPARK) study served as controls for the genome-wide association study. For replication, we used 389 unrelated Dutch/German CDH cases (71.3% isolated, 25.1% complex, and 3.6% unknown) and 4,815 ancestry-matched controls, and then performed a meta-analysis.

Results – We demonstrated 1.44-fold enrichment of predicted deleterious de novo variants in CDH cases compared to the background mutation rate. Fifteen genes, including eight novel genes, were associated with a false discovery rate <0.1 and estimated to confer relative risks for CDH ranging from 10 to 30. From common variant analyses, we identified two loci with genome-wide significance: chromosome 3p14.3/lead SNP rs55705711 (p=5.1´10-17, OR=1.65) and chromosome 7q36.3/lead SNP rs7777647 (p=1.9´10-9, OR=1.27). Lead SNPs at both loci had similar effect sizes in Europeans and Hispanics. rs55705711 resides in an intron of ERC2 (ELK2/RAB6-interacting/CAST family member 2) and adjacent to WNT5A (Wnt family member 5A), a developmental patterning gene. Epigenomic data suggest the causal variant resides in an enhancer regulating WNT5A expression. rs7777647 resides in a topologically associated domain containing five protein coding genes and a long-range cis-acting regulatory domain upstream of sonic hedgehog (SHH). Polygenic risk scores were elevated in CDH cases (complex and isolated) compared to controls.

Conclusions – De novo damaging variants likely explain 25 % of the population attributable risk for CDH, with a 2-fold enrichment of loss of function variants among complex vs isolated cases. Identification of common variant risk loci and elevated polygenic risk scores in CDH support a polygenic model as part of the CDH genetic architecture.