Evidence of Inbreeding in Hodgkin Lymphoma.

Hauke Thomsen,Sabine Ponader,Asta Försti,Per Hoffmann,Andreas Engert,Kari Hemminki,Stefan Herms,Michael Fuchs,Miguel Inacio Da Silva Filho,Elke Pogge Von Strandmann,Lewin Eisele,Riccardo Dolcetti

doi:10.1371/journal.pone.0154259

Abstract

Genome-wide association studies (GWASs) have identified several, mainly co-dominantly acting, single-nucleotide polymorphisms (SNPs) associated with Hodgkin lymphoma (HL). We searched for recessively acting disease loci by performing an analysis of runs of homozygosity (ROH) based on windows of homozygous SNP-blocks and by calculating genomic inbreeding coefficients on a SNP-wise basis. We used data from a previous GWAS with 906 cases and 1217 controls from a population with a long history of no matings between relatives. Ten recurrent ROHs were identified among 25 055 ROHs across all individuals but their association with HL was not genome-wide significant. All recurrent ROHs showed significant evidence for natural selection. As a novel finding genomic inbreeding among cases was significantly higher than among controls (P = 2.11*10−14) even after correcting for covariates. Higher inbreeding among the cases was mainly based on a group of individuals with a higher average length of ROHs per person. This result suggests a correlation of higher levels of inbreeding with higher cancer incidence and might reflect the existence of recessive alleles causing HL. Genomic inbreeding may result in a higher expression of deleterious recessive genes within a population.

Highlights

Linkage studies and genome-wide association studies (GWASs) have so far identified 8 loci to be associated with Hodgkin lymphoma (HL).[1,2,3,4,5,6]
After a stringent quality control procedure and maximizing the effective sample size, which balances the number of cases and controls best,[30] the final set consisted of 906 cases and 1 217 controls with 410 973 single-nucleotide polymorphisms (SNPs) that had a minor allele frequency (MAF)>0.05.[31]
A test was performed for any association between homozygosity and the susceptibility to HL on a SNP-by-SNP basis in our sample series

Summary

Introduction

Linkage studies and genome-wide association studies (GWASs) have so far identified 8 loci to be associated with Hodgkin lymphoma (HL).[1,2,3,4,5,6] The majority of the corresponding cancer predisposition genes function in a co-dominant manner. A single study found a linkage consistent with a recessive inheritance on chromosome 4p, as well as on chromosomes 2, 4q, 7, 11, and 17 in 44 high-risk families for HL.[7] Population-based studies have found higher sibling risks than parent-offspring risk in HL, which suggests a presence of recessive inheritance pattern besides shared childhood exposures.[8].

Methods

Results

Conclusion