Assessing the contribution of common and rare short tandem repeat (STR) variants to the risk of developing idiopathic pulmonary fibrosis (IPF)

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal lung disease with a median survival of three years. While over a dozen single nucleotide variants are associated with IPF, its genetic basis remains incomplete. This thesis investigated the role of tandem repeats (TRs) in IPF, which are often missed in standard SNP-based GWASs due to weak linkage disequilibrium. A two-stage case-control GWAS analysed whole-genome sequences (WGS) from 507 IPF cases and 174 controls in discovery, followed by replication in 1,301 cases and 3,197 controls. All individuals were of recent European ancestry, sequenced at ~30× depth using Illumina 150 bp paired-end reads (PCR-free). GangSTR was used to genotype ~174,000 autosomal common polymorphic TRs (pTRs), with 25,144 passing quality control (call-rate ≥ 99%) and tested for association. Four TRs reached genomewide significance (P value < 5×10⁻⁸). ExpansionHunter Denovo identified 12 rare TR expansions enriched in cases. Replication confirmed a common intergenic TR between MIR548I2-DRD5 genes and two rare expansions: an intergenic TR between GPATCH2L-ESSRRB and an intronic TR in SLC15A4 (P value < 5×10⁻⁸). Additionally, discovery analysis in TOPMed identified an intergenic TR between MUC5BMUC5AC and three intronic TRs in KANSL1, genes previously linked to IPF. These findings highlight TRs as potential contributors to IPF susceptibility. Evaluation of TR imputation shows that most TRs cannot be reliably imputed, underscoring the need for TR-GWAS.