Next generation sequencing of families with endometriosis identifies new genomic regions likely to contribute to heritability

Abstract

ObjectiveGenome-wide association studies (GWAS) of endometriosis have explained only a small portion of the observed heritability. By design, GWAS studies focus on older gene variants, typically those present in >3-5 % of the population. Next Generation Sequencing (NGS) on the other hand gives the opportunity to study rare, recent variants with larger effect size. However, the large number of variants identified through NGS impedes the process of prioritizing those variants. In this study, we used identity by descent (IBD) methods to study13 affected sister pairs from 7 distinct nuclear families in an effort to discover candidate genomic regions with excess mutations likely to predispose to endometriosis pathogenesis.DesignFamily-based whole genome sequencing (WGS) of 25 individuals including 19 surgically confirmed endometriosis patients of which 17 of them are siblings.Materials and MethodsPaired-end WGS was performed on HiSeq 2000 instruments (Illumina, San Diego, CA). Variant analysis was performed using the Genome-Analysis-Tool-Kit (Broad Institute). Phasing was performed using impute2 and IBD regions were identified through Germline software.ResultsTable 1ChromosomeStartEndSibling PairsLength in BasesMean Novel Variant Count/SiblingMutation Rate21004106441012234051481276140.354.96E-05295722609100405753134683144184.643.94E-0558106208290209824139147742473.415.18E-05938396065391792891378322420.72.64E-051135558904360033801344447618.294.11E-05 Open table in a new tab ConclusionGenetic variants that contribute to complex diseases range from ancient-and-common polymorphisms with minimal effects to recent-and-rare mutations predicted to have larger effects on the phenotype. Applying NGS and IBD analysis using nuclear families, we were able to identify 5 candidate endometriosis regions that show excess genetic burden. A more complete picture of the genetics of endometriosis is likely to emerge as additional WGS data are analyzed. ObjectiveGenome-wide association studies (GWAS) of endometriosis have explained only a small portion of the observed heritability. By design, GWAS studies focus on older gene variants, typically those present in >3-5 % of the population. Next Generation Sequencing (NGS) on the other hand gives the opportunity to study rare, recent variants with larger effect size. However, the large number of variants identified through NGS impedes the process of prioritizing those variants. In this study, we used identity by descent (IBD) methods to study13 affected sister pairs from 7 distinct nuclear families in an effort to discover candidate genomic regions with excess mutations likely to predispose to endometriosis pathogenesis. Genome-wide association studies (GWAS) of endometriosis have explained only a small portion of the observed heritability. By design, GWAS studies focus on older gene variants, typically those present in >3-5 % of the population. Next Generation Sequencing (NGS) on the other hand gives the opportunity to study rare, recent variants with larger effect size. However, the large number of variants identified through NGS impedes the process of prioritizing those variants. In this study, we used identity by descent (IBD) methods to study13 affected sister pairs from 7 distinct nuclear families in an effort to discover candidate genomic regions with excess mutations likely to predispose to endometriosis pathogenesis. DesignFamily-based whole genome sequencing (WGS) of 25 individuals including 19 surgically confirmed endometriosis patients of which 17 of them are siblings. Family-based whole genome sequencing (WGS) of 25 individuals including 19 surgically confirmed endometriosis patients of which 17 of them are siblings. Materials and MethodsPaired-end WGS was performed on HiSeq 2000 instruments (Illumina, San Diego, CA). Variant analysis was performed using the Genome-Analysis-Tool-Kit (Broad Institute). Phasing was performed using impute2 and IBD regions were identified through Germline software. Paired-end WGS was performed on HiSeq 2000 instruments (Illumina, San Diego, CA). Variant analysis was performed using the Genome-Analysis-Tool-Kit (Broad Institute). Phasing was performed using impute2 and IBD regions were identified through Germline software. ResultsTable 1ChromosomeStartEndSibling PairsLength in BasesMean Novel Variant Count/SiblingMutation Rate21004106441012234051481276140.354.96E-05295722609100405753134683144184.643.94E-0558106208290209824139147742473.415.18E-05938396065391792891378322420.72.64E-051135558904360033801344447618.294.11E-05 Open table in a new tab ConclusionGenetic variants that contribute to complex diseases range from ancient-and-common polymorphisms with minimal effects to recent-and-rare mutations predicted to have larger effects on the phenotype. Applying NGS and IBD analysis using nuclear families, we were able to identify 5 candidate endometriosis regions that show excess genetic burden. A more complete picture of the genetics of endometriosis is likely to emerge as additional WGS data are analyzed. Genetic variants that contribute to complex diseases range from ancient-and-common polymorphisms with minimal effects to recent-and-rare mutations predicted to have larger effects on the phenotype. Applying NGS and IBD analysis using nuclear families, we were able to identify 5 candidate endometriosis regions that show excess genetic burden. A more complete picture of the genetics of endometriosis is likely to emerge as additional WGS data are analyzed.