Abstract
A recent genome-wide association study reported a significant association between rs9828519 (G) and nonresponsiveness to interferon-beta (IFN-β) treatment and dysregulation of SLC9A9 expression in multiple sclerosis (MS) cases. We hypothesize that disease-relevant tissues are necessary to detect the effects of rs9828519-tagged SNPs on SLC9A9 expression. Here, we investigated whether SLC9A9 expression is regulated by rs9828519-tagged SNPs in human brain tissue. We used HaploReg to identify the proxy SNPs of the rs9828519 variant based on linkage disequilibrium information from the 1000 Genomes Project. We evaluated the potential association between these SNPs and SLC9A9 expression using multiple expression quantitative trait loci datasets including 10 brain regions of 134 individuals from Braineac, 2 brain regions of 773 samples from brain expression GWAS datasets, and 12 brain regions from the GTEx. We discovered differential SLC9A9 expression in different brain regions and identified 15 rs9828519-tagged SNPs that significantly regulated SLC9A9 expression only in occipital cortex, intralobular white matter, and substantia nigra. Our results advance the understanding of the involvement of SLC9A9 and rs9828519 mechanisms in MS.
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References
Damotte V, Guillot-Noel L, Patsopoulos NA, Madireddy L, El Behi M, De Jager PL, Baranzini SE, Cournu-Rebeix I et al (2014) A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility. Genes Immun 15:126–132
International Multiple Sclerosis Genetics Consortium (2013) Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls. Am J Hum Genet 92:854–865
Liu G, Zhang F, Jiang Y, Hu Y, Gong Z, Liu S, Chen X, Jiang Q, et al. (2016) Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways. Mult Scler. doi:10.1177/1352458516649038
Briggs FB, Leung LJ, Barcellos LF (2014) Annotation of functional variation within non-MHC MS susceptibility loci through bioinformatics analysis. Genes Immun 15:466–476
Esposito F, Sorosina M, Ottoboni L, Lim ET, Replogle JM, Raj T, Brambilla P, Liberatore G et al (2015) A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann Neurol 78:115–127
Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN et al (2012) Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet 8:e1002707
Liu G, Bao X, Wang R (2015) Expression quantitative trait loci regulate HNF4A and PTBP1 expression in human brains. Proc Natl Acad Sci U S A 112:E3975
Bao X, Liu G, Jiang Y, Jiang Q, Liao M, Feng R, Zhang L, Ma G et al (2015) Cell adhesion molecule pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in Alzheimer’s disease brains. Neurobiol Aging 36:2904 e2901–2904 e2907
Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934
Ramasamy A, Trabzuni D, Guelfi S, Varghese V, Smith C, Walker R, De T, Coin L et al (2014) Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 17:1418–1428
Human genomics (2015) The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348:648–660
GTEx Consortium (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45:580–585
Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R (2013) Functional evaluation of autism-associated mutations in NHE9. Nat Commun 4:2510
Markunas CA, Quinn KS, Collins AL, Garrett ME, Lachiewicz AM, Sommer JL, Morrissey-Kane E, Kollins SH et al (2010) Genetic variants in SLC9a9 are associated with measures of attention-deficit/hyperactivity disorder symptoms in families. Psychiatr Genet 20:73–81
Schwede M, Garbett K, Mirnics K, Geschwind DH, Morrow EM (2014) Genes for endosomal NHE6 and NHE9 are misregulated in autism brains. Mol Psychiatry 19:277–279
Acknowledgments
This work was financially supported by the National Basic Research Program of China (2013CB966900 to F. D. S); the National Natural Science Foundation of China (81300945 to G. Y. L., 61571152 to Q.H.J., and 81571600, 81322018, 81273287 and 81100887 to J. W. H.); the Youth Top-notch Talent Support Program; the National Key Clinical Specialty Construction Project of China, and the Major State Research Development Program of China (2016YFC1202302 to Q.H.J.).
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Guiyou Liu and Fang Zhang contributed equally to this work.
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Liu, G., Zhang, F., Hu, Y. et al. Genetic Variants and Multiple Sclerosis Risk Gene SLC9A9 Expression in Distinct Human Brain Regions. Mol Neurobiol 54, 6820–6826 (2017). https://doi.org/10.1007/s12035-016-0208-5
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DOI: https://doi.org/10.1007/s12035-016-0208-5