Abstract
A sizable fraction of testicular germ cell tumour (TGCT) risk is expected to be explained by heritable factors. Recent genome-wide association studies (GWAS) have successfully identified a number of common SNPs associated with TGCT. It is however, unclear how much common variation there is left to be accounted for by other, yet to be identified, common SNPs and what contribution common genetic variation makes to the heritable risk of TGCT. We approached this question using two complimentary analytical techniques. We undertook a population-based analysis of the Swedish family-cancer database, through which we estimated that the heritability of TGCT at 48.9% (CI:47.2%–52.3%). We also applied Genome-Wide Complex Trait Analysis to 922 cases and 4,842 controls to estimate the heritability of TGCT. The heritability explained by known common risk SNPs identified by GWAS was 9.1%, whereas the heritability explained by all common SNPs was 37.4% (CI:27.6%–47.2%). These complementary findings indicate that the known TGCT SNPs only explain a small proportion of the heritability and many additional common SNPs remain to be identified. The data also suggests that a fraction of the heritability of TGCT is likely to be explained by other classes of genetic variation, such as rare disease-causing alleles.
Highlights
A sizable fraction of testicular germ cell tumour (TGCT) risk is expected to be explained by heritable factors
In this study we present results from both genomic and population-based techniques, and estimate the heritability of Testicular germ cell tumour (TGCT) to be in a consistent range of 37%–49%
The higher estimate from the population-based approach is a logical outcome, given that the pedigree data includes the contribution of all causal variants, whereas the genomic approach can only account for the variation explained by variants in linkage disequilibrium (LD) with genotyped SNPs
Summary
A sizable fraction of testicular germ cell tumour (TGCT) risk is expected to be explained by heritable factors. The success of recent GWAS, the heritable nature of TGCT is poorly understood, both in terms of its magnitude and genetic architecture Emergent statistical methods such as genome-wide complex trait analysis (GCTA) and phenotype correlation-genotype correlation (PCGC) regression allow the heritability ascribable to all common SNPs to be estimated from GWAS datasets[19,20,21]. These methodologies are complimentary to population based analyses, which quantify heritability from the clustering of disease within families. We employ both methodologies to estimate the heritability of TGCT, by firstly performing an analysis of the Swedish population registry, comprising 15.7 million individuals and secondly conducting a GCTA analysis of a GWAS dataset of 6,000 individuals
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