• Qi Liu, Yuan Zhou, Joy D Cogan, Daphne B Mitchell, Quanhu Sheng, Shilin Zhao, Youhuang Bai, Kristen K Ciombor, Carleen M Sabusap, M Merced Malabanan, Cheryl R Markin, Katrina Douglas, Guixiao Ding, Nicholas E Banovich, Deborah A Nickerson, Elizabeth E Blue, Michael J Bamshad, Kevin K Brown, David A Schwartz, John A Phillips, Ruben Martinez-Barricarte, Margaret L Salisbury, Yu Shyr, James E Loyd, Jonathan A Kropski, and Timothy S Blackwell.
• Department of Biostatistics.
• Am. J. Respir. Crit. Care Med. 2023 May 15; 207 (10): 134513571345-1357.

AbstractRationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9-23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families-including SYDE1, SERPINB8, GPR87, and NETO1-and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.

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