The impact of rare and low-frequency genetic variants in common disease

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Abstract

Despite thousands of genetic loci identified to date, a large proportion of genetic variation predisposing to complex disease and traits remains unaccounted for. Advances in sequencing technology enable focused explorations on the contribution of low-frequency and rare variants to human traits. Here we review experimental approaches and current knowledge on the contribution of these genetic variants in complex disease and discuss challenges and opportunities for personalised medicine.

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The online version of this article (doi:10.1186/s13059-017-1212-4) contains supplementary material, which is available to authorized users.

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Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

J Hugot, M Chamaillard, H Zouali … (2001)

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

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Rare-variant association analysis: study designs and statistical tests.

Seunggeung Lee, Gonçalo R Abecasis, Michael Boehnke … (2014)

Despite the extensive discovery of trait- and disease-associated common variants, much of the genetic contribution to complex traits remains unexplained. Rare variants can explain additional disease risk or trait variability. An increasing number of studies are underway to identify trait- and disease-associated rare variants. In this review, we provide an overview of statistical issues in rare-variant association studies with a focus on study designs and statistical tests. We present the design and analysis pipeline of rare-variant studies and review cost-effective sequencing designs and genotyping platforms. We compare various gene- or region-based association tests, including burden tests, variance-component tests, and combined omnibus tests, in terms of their assumptions and performance. Also discussed are the related topics of meta-analysis, population-stratification adjustment, genotype imputation, follow-up studies, and heritability due to rare variants. We provide guidelines for analysis and discuss some of the challenges inherent in these studies and future research directions. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS

Iuliana Ionita-Laza, Kenneth McCallum, Bin Xu … (2016)

Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequence. Such annotations can play a critical role in identifying putatively causal variants among the abundant natural variation that occurs at a locus of interest. The main challenges in using these various annotations include their large numbers, and their diversity. Here we develop an unsupervised approach to integrate these different annotations into one measure of functional importance (Eigen), that, unlike most existing methods, is not based on any labeled training data. We show that the resulting meta-score has better discriminatory ability using disease associated and putatively benign variants from published studies (in both coding and noncoding regions) compared with the recently proposed CADD score. Across varied scenarios, the Eigen score performs generally better than any single individual annotation, representing a powerful single functional score that can be incorporated in fine-mapping studies.

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Author and article information

Contributors

Nicole Soranzo: ns6@sanger.ac.uk

Journal

Journal ID (nlm-ta): Genome Biol

Journal ID (iso-abbrev): Genome Biol

Title: Genome Biology

Publisher: BioMed Central (London )

ISSN (Print): 1474-7596

ISSN (Electronic): 1474-760X

Publication date (Electronic): 27 April 2017

Publication date PMC-release: 27 April 2017

Publication date Collection: 2017

Volume: 18

Electronic Location Identifier: 77

Affiliations

[1 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, , Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, ; Hinxton, CB10 1HH UK

[2 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Haematology, , University of Cambridge, ; Hills Rd, Cambridge, CB2 0AH UK

[3 ]ISNI 0000000121885934, GRID grid.5335.0, The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, , University of Cambridge, Strangeways Research Laboratory, ; Wort’s Causeway, Cambridge, CB1 8RN UK

Article

Publisher ID: 1212

DOI: 10.1186/s13059-017-1212-4

PMC ID: 5408830

PubMed ID: 28449691

SO-VID: 9554407f-9fdb-40d6-8b33-0107b673493c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;

Award ID: WT098051

Award ID: WT091310

Award Recipient : Nicole Soranzo

Funded by: Seventh Framework Programme (BE)

Award ID: 257082

Award Recipient : Nicole Soranzo

Funded by: Seventh Framework Programme (BE)

Award ID: HEALTH-F5-2011-282510

Award Recipient : Nicole Soranzo

Funded by: National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge in partnership with NHS Blood and Transplant (NHSBT)

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The impact of rare and low-frequency genetic variants in common disease

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Genomic Prediction

Most cited references 74

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

Rare-variant association analysis: study designs and statistical tests.

A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS

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Cited by 123

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