Biology subjects

Bigio, B.

Publications and source records attributed to Bigio, B..

5 recordsLinked to original sources

bioRxiv2020

Detection of homozygous and hemizygous partial exon deletions by whole-exome sequencing

The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in typical laboratory cohorts that are generated over time under different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder-opt to identify HMZ partial deletions of exons that are otherwise undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in laboratory cohorts, which are typically heterogeneous.

bioinformatics↗

bioRxiv2020

Controlling for Human Population Stratification in Rare Variant Association Studies

Population stratification is a strong confounding factor in human genetic association studies. In analyses of rare variants, the main correction strategies based on principal components (PC) and linear mixed models (LMM), may yield conflicting conclusions, due to both the specific type of structure induced by rare variants and the particular statistical features of association tests. Studies evaluating these approaches generally focused on specific situations with limited types of simulated structure and large sample sizes. We investigated the properties of several correction methods in the context of a large simulation study using real exome data, and several within- and between- continent stratification scenarios. We also considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. In this context, we focused on a genetic model with a phenotype driven by rare deleterious variants well suited for a burden test. For analyses of large samples, we found that accounting for stratification was more difficult with a continental structure than with a worldwide structure. LMM failed to maintain a correct type I error in many scenarios, whereas PCs based on common variants failed only in the presence of extreme continental stratification. When a sample of 50 cases was considered, an inflation of type I errors was observed with PC for small numbers of controls ([≤]100), and with LMM for large numbers of controls ([≥]1000). We also tested a promising novel adapted local permutation method (LocPerm), which maintained a correct type I error in all situations. All approaches capable of correcting for stratification properly had similar powers for detecting actual associations pointing out that the key issue is to properly control type I errors. Finally, we found that adding a large panel of external controls (e.g. extracted from publicly available databases) was an efficient way to increase the power of analyses including small numbers of cases, provided an appropriate stratification correction was used. Author SummaryGenetic association studies focusing on rare variants using next generation sequencing (NGS) data have become a common strategy to overcome the shortcomings of classical genome-wide association studies for the analysis of rare and common diseases. The issue of population stratification remains however a substantial question that has not been fully resolved when analyzing NGS data. In this work, we propose a comprehensive evaluation of the main strategies to account for stratification, that are principal components and linear mixed model, along with a novel approach based on local permutations (LocPerm). We compared these correction methods in many different settings, considering several types of population structures, sample sizes or types of variants. Our results highlighted important limitations of some classical methods as those using principal components (in particular in small samples) and linear mixed models (in several situations). In contrast, LocPerm maintained a correct type I error in all situations. Also, we showed that adding a large panel of external controls, e.g coming from publicly available databases, is an efficient strategy to increase the power of an analysis including a low number of cases, as long as an appropriate stratification correction is used. Our findings provide helpful guidelines for many researchers working on rare variant association studies.

genetics↗

bioRxiv2020

A genome-wide case-only test for the detection of digenic inheritance in human exomes

Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a novel two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene x gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment and bias of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we validated our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients. Significance statementDespite a growing number of reports of rare disorders not fully explained by monogenic lesions, digenic inheritance has been reported for only 54 diseases to date. The very few existing methods for detecting gene x gene interactions from next-generation sequencing data were generally studied in rare-variant association studies with limited simulation analyses for short genomic regions, under a case-control design. We describe the first case-only approach designed specifically to search for digenic inheritance, which avoids recruitment and bias related to controls. We show, through both extensive simulation studies on real WES datasets and application to a real example of craniosynostosis, that our method is robust and powerful for the genome-wide identification of digenic lesions.

genetics↗

bioRxiv2020

Taking population stratification into account by local permutations in rare-variant association studies on small samples

Many methods for rare variant association studies require permutations to assess the significance of tests. Standard permutations assume that all individuals are exchangeable and do not take population stratification (PS), a known confounding factor in genetic studies, into account. We propose a novel strategy, LocPerm, in which individuals are permuted only with their closest ancestry-based neighbors. We performed a simulation study, focusing on small samples, to evaluate and compare LocPerm with standard permutations and classical adjustment on first principal components. Under the null hypothesis, LocPerm was the only method providing an acceptable type I error, regardless of sample size and level of stratification. The power of LocPerm was similar to that of standard permutation in the absence of PS, and remained stable in different PS scenarios. We conclude that LocPerm is a method of choice for taking PS and/or small sample size into account in rare variant association studies.

genomics↗

bioRxiv2017

IRF4 haploinsufficiency in a family with Whipples disease

The pathogenesis of Whipples disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected with Tropheryma whipplei (Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant of IRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rare IRF4 alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found that IRF4 had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at the IRF4 locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.

immunology↗