Abstract
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance–a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.
Highlights
Rare risk variants have been suggested as a source of missing heritability in the majority of complex traits [1,2,3]
While high-risk pedigree (HRP) have been successful for relatively simple traits, genetic heterogeneity remains a major obstacle that reduces the effectiveness of HRPs for gene mapping in complex traits [12,13]
We developed a novel strategy to identify segregating chromosomal segments shared by subsets of cases in HRPs
Summary
Rare risk variants have been suggested as a source of missing heritability in the majority of complex traits [1,2,3]. High-risk pedigrees (HRPs) are a mainstay for identifying rare, highly penetrant, Mendelian-like, causal variants [4,5,6,7,8,9,10,11]. Challenging is mapping regulatory variants, likely to be important for complex traits, necessitating interrogation outside the well-annotated, coding regions of the genome [14,15]. Localizing chromosomal regions to target the search for rare, risk variants will be instrumental in mapping them. Key to the utility of the method is the derivation of significance thresholds for interpretation
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