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Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis
INTRODUCTION: Although it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon seque...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203956/ https://www.ncbi.nlm.nih.gov/pubmed/25267259 http://dx.doi.org/10.1186/s13075-014-0447-7 |
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author | Bang, So-Young Na, Young-Ji Kim, Kwangwoo Joo, Young Bin Park, Youngho Lee, Jaemoon Lee, Sun-Young Ansari, Adnan A Jung, Junghee Rhee, Hwanseok Lee, Jong-Young Han, Bok-Ghee Ahn, Sung-Min Won, Sungho Lee, Hye-Soon Bae, Sang-Cheol |
author_facet | Bang, So-Young Na, Young-Ji Kim, Kwangwoo Joo, Young Bin Park, Youngho Lee, Jaemoon Lee, Sun-Young Ansari, Adnan A Jung, Junghee Rhee, Hwanseok Lee, Jong-Young Han, Bok-Ghee Ahn, Sung-Min Won, Sungho Lee, Hye-Soon Bae, Sang-Cheol |
author_sort | Bang, So-Young |
collection | PubMed |
description | INTRODUCTION: Although it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon sequencing of RA in Korea. METHODS: We analyzed targeted exon sequencing data of 398 genes selected from a multifaceted approach in Korean RA patients (n = 1,217) and controls (n = 717). We conducted a single-marker association test and a gene-based analysis of rare variants. For meta-analysis or enrichment tests, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n = 4,799) or immunochip data (n = 4,722). RESULTS: After stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case controls. We identified 13 nonsynonymous variants with nominal association in single-variant association tests. In a meta-analysis, we did not find any novel variant with genome-wide significance for RA risk. Using a gene-based approach, we identified 17 genes with nominal burden signals. Among them, VSTM1 showed the greatest association with RA (P = 7.80 × 10(−4)). In the enrichment test using Korean GWAS, although the significant signal appeared to be driven by total genic variants, we found no evidence for enriched association of coding variants only with RA. CONCLUSIONS: We were unable to identify rare coding variants with large effect to explain the missing heritability for RA in the current targeted resequencing study. Our study raises skepticism about exon sequencing of targeted genes for complex diseases like RA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-014-0447-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4203956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42039562014-10-22 Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis Bang, So-Young Na, Young-Ji Kim, Kwangwoo Joo, Young Bin Park, Youngho Lee, Jaemoon Lee, Sun-Young Ansari, Adnan A Jung, Junghee Rhee, Hwanseok Lee, Jong-Young Han, Bok-Ghee Ahn, Sung-Min Won, Sungho Lee, Hye-Soon Bae, Sang-Cheol Arthritis Res Ther Research Article INTRODUCTION: Although it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon sequencing of RA in Korea. METHODS: We analyzed targeted exon sequencing data of 398 genes selected from a multifaceted approach in Korean RA patients (n = 1,217) and controls (n = 717). We conducted a single-marker association test and a gene-based analysis of rare variants. For meta-analysis or enrichment tests, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n = 4,799) or immunochip data (n = 4,722). RESULTS: After stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case controls. We identified 13 nonsynonymous variants with nominal association in single-variant association tests. In a meta-analysis, we did not find any novel variant with genome-wide significance for RA risk. Using a gene-based approach, we identified 17 genes with nominal burden signals. Among them, VSTM1 showed the greatest association with RA (P = 7.80 × 10(−4)). In the enrichment test using Korean GWAS, although the significant signal appeared to be driven by total genic variants, we found no evidence for enriched association of coding variants only with RA. CONCLUSIONS: We were unable to identify rare coding variants with large effect to explain the missing heritability for RA in the current targeted resequencing study. Our study raises skepticism about exon sequencing of targeted genes for complex diseases like RA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-014-0447-7) contains supplementary material, which is available to authorized users. BioMed Central 2014-09-30 2014 /pmc/articles/PMC4203956/ /pubmed/25267259 http://dx.doi.org/10.1186/s13075-014-0447-7 Text en © Bang et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. |
spellingShingle | Research Article Bang, So-Young Na, Young-Ji Kim, Kwangwoo Joo, Young Bin Park, Youngho Lee, Jaemoon Lee, Sun-Young Ansari, Adnan A Jung, Junghee Rhee, Hwanseok Lee, Jong-Young Han, Bok-Ghee Ahn, Sung-Min Won, Sungho Lee, Hye-Soon Bae, Sang-Cheol Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
title | Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
title_full | Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
title_fullStr | Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
title_full_unstemmed | Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
title_short | Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
title_sort | targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203956/ https://www.ncbi.nlm.nih.gov/pubmed/25267259 http://dx.doi.org/10.1186/s13075-014-0447-7 |
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