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Master of Public Health

The Genetic Landscape of Familial Pulmonary Fibrosis

AUTHORS

Liu Q , Zhou Y , Cogan JD , Mitchell DB , Sheng Q , Zhao S , Bai Y , Ciombor KK , Sabusap CM , Markin CR , Douglas K , Ding G , Banovich NE , Nickerson DA , Blue EE , Bamshad MJ , Brown KK , Schwartz DA , Phillips JA , Martinez-Barricarte R , Salisbury ML , Shyr Y , Loyd JE , Kropski JA , Blackwell TS , . American journal of respiratory and critical care medicine. 2023 1 9; ().

ABSTRACT

RATIONALE AND OBJECTIVES: Up to 20% of idiopathic interstitial lung disease is familial, referred to as Familial Pulmonary Fibrosis (FPF). We performed an integrated analysis of FPF genetic risk by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds.

METHODS: We performed whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds, followed by co-segregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell type enrichment analysis, and co-expression network construction.

MEASUREMENTS AND MAIN RESULTS: We 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. We identified new candidate genes in a small number of families, including SYDE1, SERPINB8, GPR87, and NETO1, and developed tools 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, we discovered that expression of RV-containing genes was enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells.

CONCLUSIONS: In the most comprehensive FPF genetic study to date, we defined the prevalence of RVs in known FPF-related genes and identified new candidate genes and pathways relevant to FPF. However, we did not identify new RV-containing genes shared across multiple kindreds, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.

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