Unravelling traits with complex inheritance mode: a gene panel perspective

Abstract

Although gene panels for complex phenotypes target genes contributing significantly to phenotypic variation, identifying causal mutations remains challenging. We aimed to define the process of analysing gene panel data to uncover genomic insights for traits with complex inheritance. The implemented procedure included the exploration of (i) the association between phenotypic variability and the variability of SNPs within genes, (ii) the association attributed to specific variants, (iii) causality potential by analysing the genomic context in the vicinity of the significantly associated SNPs (iii_a) either through clustering - to identify variants with genotypic patterns similar to the significant SNPs, or (iii_b) through smoothing the set of original P values to incorporate the information on the impact of the particular mutations, as expressed by the SNP-specific PhRED-CADD scores. This procedure was applied to the data from the obesity gene panel. No significant gene-level associations were found. However, the SNP-level results were promising in narrowing down the initially available set of variants to determine the true causal mutations. We introduced a procedure for analysing gene panel data to identify potentially causal mutations for phenotypes with complex inheritance patterns. The procedure allows for narrowing down the originally available set of variants offered by a gene panel, consisting of genes important for the phenotype under study, to SNPs that have a statistically and genomically validated potential to be causal in modifying protein structure.