Genetic variant representation, annotation and prioritization in the post-GWAS era

Li, Mulin Jun; Sham, Pak Chung; Wang, Junwen

doi:10.1038/cr.2012.106

Letter to the Editor
Published: 17 July 2012

Genetic variant representation, annotation and prioritization in the post-GWAS era

Mulin Jun Li^1,2,
Pak Chung Sham^3,4,5 &
Junwen Wang^1,2,3

Cell Research volume 22, pages 1505–1508 (2012)Cite this article

3897 Accesses
33 Citations
Metrics details

Subjects

Since 2005¹, genome-wide association studies (GWAS) and Next Generation Sequencing (NGS) have opened up new realms of investigation into the association between different diseases/traits and a large number of genetic loci. To date, more than 1 200 GWAS on over 250 traits have been published². The advent of NGS and affordable whole genome and exome sequencing has accelerated the discovery of the genes underlying Mendelian diseases and has also enhanced our ability to detect rare variants. These variants may explain the missing heritability of common diseases and specific traits³.

To discriminate the true trait/disease-associated SNPs (TASs) from the large number of loci discovered by GWAS and NGS studies, we need further downstream statistical and bioinformatics analyses⁴. Variant visualization, functional annotation and prioritization are vital for determining the true associations between genetic markers and diseases/traits, from the multiple signals many of which represent chance findings. In addition, an increasing number of requirements, such as clarity, diversity and interactivity, pose demands on data visualization^5,6. Thorough functional annotations based on genomic location and potential biological effects are needed, especially for markers with moderate effects located in regulatory regions (e.g., non-coding RNAs, enhancers and promoters, and those in evolutionarily conserved regions)^7,8,9, and for markers that have functional interactions with other TASs¹⁰. Comprehensive variant annotation will undoubtedly accelerate this process. Existing bioinformatics tools such as ANNOVAR¹¹ and VAAST¹² use genomic mapping to produce variant annotation, but few tools focus on the potential functional effects of TASs. Importantly, to properly distinguish the true association of TASs from the huge amount of GWAS signals, particularly for hidden TASs with moderate P-value, an annotation-based prioritizing process is required. Therefore, tools that can visualize, annotate and prioritize such data are urgently needed.

References

Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308:385–389.
Article CAS Google Scholar
Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009; 106:9362–9367.
Article CAS Google Scholar
Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12:745–755.
Article CAS Google Scholar
Wang K, Li M, Hakonarson H . Analysing biological pathways in genome-wide association studies. Nat Rev Genet 2010; 11:843–854.
Article CAS Google Scholar
Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol 2011; 29:24–26.
Article CAS Google Scholar
Pruim RJ, Welch RP, Sanna S, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26:2336–2337.
Article CAS Google Scholar
Wang J . A database of genetic variants in microRNA genes and their putative functional roles in gene regulation. Hum Mutat 2012; 33:vii–vii.
Article Google Scholar
Wang W, Wei Z, Lam TW, Wang JW . Next generation sequencing has lower sequence coverage and poorer SNP-detection capability in the regulatory regions. Sci Rep 2011; 1:55.
Article Google Scholar
Wei Z, Jensen ST . GAME: detecting cis-regulatory elements using a genetic algorithm. Bioinformatics 2006; 22:1577–1584.
Article CAS Google Scholar
Hu X, Liu Q, Zhang Z, et al. SHEsisEpi, a GPU-enhanced genome-wide SNP-SNP interaction scanning algorithm, efficiently reveals the risk genetic epistasis in bipolar disorder. Cell Res 2010; 20:854–857.
Article Google Scholar
Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38:e164
Article Google Scholar
Yandell M, Huff C, Hu H, et al. A probabilistic disease-gene finder for personal genomes. Genome Res 2011; 21:1529–1542.
Article CAS Google Scholar
Krzywinski M, Schein J, Birol I, et al. Circos: an information aesthetic for comparative genomics. Genome Res 2009; 19:1639–1645.
Article CAS Google Scholar
Li MJ, Wang P, Liu X, et al. GWASdb: a database for human genetic variants identified by genome-wide association studies. Nucleic Acids Res 2012; 40 (Database issue):D1047–D1054.
Article CAS Google Scholar

Download references

Acknowledgements

This study was supported by grants from the Research Grants Council (781511M, 778609M, N_HKU752/10, AoE M-04/04), Food and Health Bureau (10091262) of Hong Kong, and The University of Hong Kong Strategic Research Theme on Genomics.

Author information

Authors and Affiliations

Department of Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Mulin Jun Li & Junwen Wang
Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, 518057, Guangdong, China
Mulin Jun Li & Junwen Wang
Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Pak Chung Sham & Junwen Wang
Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Pak Chung Sham
The State Key Laboratory in Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China
Pak Chung Sham

Authors

Mulin Jun Li
View author publications
Search author on:PubMed Google Scholar
Pak Chung Sham
View author publications
Search author on:PubMed Google Scholar
Junwen Wang
View author publications
Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Junwen Wang.

Additional information

( Supplementary information is linked to the online version of the paper on the Cell Research website.)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, M., Sham, P. & Wang, J. Genetic variant representation, annotation and prioritization in the post-GWAS era. Cell Res 22, 1505–1508 (2012). https://doi.org/10.1038/cr.2012.106

Download citation

Published: 17 July 2012
Issue date: October 2012
DOI: https://doi.org/10.1038/cr.2012.106

This article is cited by

HPOAnnotator: improving large-scale prediction of HPO annotations by low-rank approximation with HPO semantic similarities and multiple PPI networks
- Junning Gao
- Lizhi Liu
- Shanfeng Zhu
BMC Medical Genomics (2019)
Principles and methods of in-silico prioritization of non-coding regulatory variants
- Phil H. Lee
- Christian Lee
- Mark Daly
Human Genetics (2018)
Long non-coding RNAs as novel players in β cell function and type 1 diabetes
- Aashiq H. Mirza
- Simranjeet Kaur
- Flemming Pociot
Human Genomics (2017)
Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes
- Dan-Dan Zhang
- Wen-Tian Wang
- De-Pei Liu
Scientific Reports (2017)
Association of common variants in the calcium-sensing receptor gene with serum calcium levels in East Asians
- Nadimuthu Vinayagamoorthy
- Seon-Hee Yim
- Yeun-Jun Chung
Journal of Human Genetics (2015)

Subjects

Log in or create a free account to read this content