IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

Booth, David R., Heard, Robert N., Stewart, Graeme J., Goris, An, Dobosi, Rita, Dubois, Bénédicte, Lorentzen, Åslaug R., Celius, Elisabeth C., Harbo, Hanne F., Spurkland, Anne, Olsson, Tomas, Kockum, Ingrid, Link, Jenny, Hillert, Jan, Ban, Maria, Baker, Amie, Sawcer, Stephen, Compston, Alastair, Mihalova, Tania, Strange, Richard, Hawkins, Clive, Ingram, Gillian, Robertson, Neil ORCID: https://orcid.org/0000-0002-5409-4909, De Jager, Philip L., Hafler, David A., Barcellos, Lisa F., Ivinson, Adrian J., Pericak-Vance, Margaret, Oksenberg, Jorge R., Hauser, Stephen L., McCauley, Jacob L., Sexton, David and Haines, Jonathan 2010. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes and Immunity 11 (5) , pp. 397-405. 10.1038/gene.2010.28

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Abstract

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 × 10−9), IL12A (P=3.08 × 10−8) and MPHOSPH9/CDK2AP1 (P=3.96 × 10−8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 × 10−5) and in peripheral blood mononuclear cells from subjects with MS (P=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics Q Science > QR Microbiology > QR180 Immunology
Uncontrolled Keywords:	multiple sclerosis, susceptibility loci, eQTL
Publisher:	Nature Publishing Group
ISSN:	1466-4879
Last Modified:	20 Oct 2022 08:56
URI:	https://orca.cardiff.ac.uk/id/eprint/30092

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