Computational Analysis of Breast Cancer GWAS Loci Identifies the Putative Deleterious Effect of STXBP4 and ZNF404 Gene Variants.

Autor: Masoodi TA; Department of Biotechnology, K L University, Guntur, Andhra Pradesh, India.; Department of Biotechnology, Hyderabad Science Society, Hyderabad, 500004, India., Banaganapalli B; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.; Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdul Aziz University, Jeddah., Vaidyanathan V; Discipline of Nutrition and Dietetics, FMHS, University of Auckland, Auckland, 1023, New Zealand., Talluri VR; Department of Biotechnology, K L University, Guntur, Andhra Pradesh, India.; Prof. TNA Innovation Center, Varsha Bioscience and Technology India Private Limited, Hyderabad, India., Shaik NA; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.; Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdul Aziz University, Jeddah.
Jazyk: angličtina
Zdroj: Journal of cellular biochemistry [J Cell Biochem] 2017 Dec; Vol. 118 (12), pp. 4296-4307. Date of Electronic Publication: 2017 May 25.
DOI: 10.1002/jcb.26080
Abstrakt: The genome-wide association studies (GWAS) have enabled us in identifying different breast cancer (BC) susceptibility loci. However, majority of these are non-coding variants with no annotated biological function. We investigated such 78 noncoding genome wide associated SNPs of BC and further expanded the list to 2,162 variants with strong linkage-disequilibrium (LD, r 2 ≥0.8). Using multiple publically available algorithms such as CADD, GWAVA, and FATHAMM, we classified all these variants into deleterious, damaging, or benign categories. Out of total 2,241 variants, 23 (1.02%) variants were extreme deleterious (rank 1), 70 (3.12%) variants were deleterious (rank 2), and 1,937 (86.43%) variants were benign (rank 3). The results show 14% of lead or associated variants are under strong negative selection (GERP++ RS ≥2), and ∼22% are under balancing selection (Tajima's D score >2) in CEU population of 1KGP-the regions being positively selected (GERP++ RS <0) in mammalian evolution. The expression quantitative trait loci of highest deleteriously ranked genes were tested on relevant adipose and breast tissues, the results of which were extended for protein expression on breast tissues. From the concordance analysis of ranking system of GWAVA, CADD, and FATHMM, eQTL and protein expression, we identified the deleterious SNPs localized in STXBP4 and ZNF404 genes which might play a role in BC development by dysregulating its gene expression. This simple approach will be easier to implement and to prioritize large scale GWAS data for variety of diseases and link to the potentially unrecognized functional roles of genes. J. Cell. Biochem. 118: 4296-4307, 2017. © 2017 Wiley Periodicals, Inc.
(© 2017 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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