Population genomics in a disease targeted primary cell model.

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• Complex traits are influenced by genetic variants in noncoding DNA, affecting gene regulation in a cell-type specific manner.
• Understanding cell type-specific regulatory effects is crucial for dissecting disease associations and prioritizing genetic loci identified through genome-wide association studies (GWAS).

Purpose of the Study:

• To conduct an expression quantitative trait loci (eQTL) study in primary human osteoblasts (HOb) to identify genetic variants associated with bone mineral density (BMD).
• To compare the enrichment of cis-eQTLs in HOb with lymphoblastoid cell lines (LCLs) for prioritizing GWAS hits.
• To validate novel BMD loci identified through eQTL analysis in independent cohorts.

Main Methods:

• Performed an eQTL study on primary human osteoblasts (HOb) from 95 Swedish donors.
• Combined HOb eQTL data with GWAS data for BMD, testing top BMD-associated single nucleotide polymorphisms (SNPs) for cis-association in HOb and publicly available LCL data.
• Validated top BMD loci with strong cis-eQTL effects in HOb using staged cohorts (Swedish MrOS Cohort and Rotterdam Study).

Main Results:

• Human osteoblasts (HOb) showed a threefold greater enrichment of converging cis-eQTLs compared to lymphoblastoid cell lines (LCLs).
• Identified two novel BMD loci, SRR and MSH3, through validation in the Swedish MrOS Cohort.
• Converging evidence for BMD association was found at the SRR locus (17p13.3) in the Rotterdam Study, with fine-mapping implicating the proximal promoter of the SRR gene.

Conclusions:

• Primary human osteoblasts are a more relevant cell model than LCLs for identifying regulatory variants associated with BMD.
• The study successfully identified and validated novel genetic loci (SRR and MSH3) influencing BMD.
• Utilizing disease-relevant primary cells enhances the prioritization and validation of GWAS findings for complex traits.