Rare variant association testing in the non-coding genome
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REVIEW
Rare variant association testing in the non‑coding genome Ozvan Bocher1 · Emmanuelle Génin1,2 Received: 22 April 2020 / Accepted: 29 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The development of next-generation sequencing technologies has opened-up some new possibilities to explore the contribution of genetic variants to human diseases and in particular that of rare variants. Statistical methods have been developed to test for association with rare variants that require the definition of testing units and, in these testing units, the selection of qualifying variants to include in the test. In the coding regions of the genome, testing units are usually the different genes and qualifying variants are selected based on their functional effects on the encoded proteins. Extending these tests to the non-coding regions of the genome is challenging. Testing units are difficult to define as the non-coding genome organisation is still rather unknown. Qualifying variants are difficult to select as the functional impact of non-coding variants on gene expression is hard to predict. These difficulties could explain why very few investigators so far have analysed the non-coding parts of their whole genome sequencing data. These non-coding parts yet represent the vast majority of the genome and some studies suggest that they could play a major role in disease susceptibility. In this review, we discuss recent experimental and statistical developments to gain knowledge on the non-coding genome and how this knowledge could be used to include rare non-coding variants in association tests. We describe the few studies that have considered variants from the non-coding genome in association tests and how they managed to define testing units and select qualifying variants.
Introduction The development of high throughput genome sequencing technologies has opened-up new perspectives in the study of human diseases, including common diseases (Petersen et al. 2017), with the possibility to explore the full range of variant allele frequencies. Indeed, genome-wide association studies (GWAS) that were conducted before the sequencing era using SNP-chip data only explored the role of common genetic variants on disease susceptibility. With sequencing data, it is now possible to study the role played by rare variants and to explore the common disease multiple rare variants paradigm (Saint Pierre and Génin 2014). Under this paradigm, it is anticipated that different rare genetic variants * Ozvan Bocher ozvan.bocher@univ‑brest.fr * Emmanuelle Génin [email protected] 1
Génétique, Génomique Fonctionnelle Et Biotechnologies, Faculté de Médecine, Univ Brest, Inserm, Inserm UMR1078, Bâtiment E‑IBRBS 2ieme étage, 22 avenue Camille Desmoulins, 29238 Brest Cedex 3, France
CHU Brest, Brest, France
2
located within one or a few genes could contribute to disease susceptibility with stronger effects than common variants. To test this hypothesis, novel association tests were developed to analyse exome
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