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Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data

Joanne H Wang1, Derek Pappas1, Philip L De Jager23, Daniel Pelletier1, Paul IW de Bakker34, Ludwig Kappos5, Chris H Polman6, Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)7, Lori B Chibnik2, David A Hafler8, Paul M Matthews9, Stephen L Hauser110, Sergio E Baranzini1 and Jorge R Oksenberg110*

Author Affiliations

1 Department of Neurology, University of California San Francisco, San Francisco, CA 94143-0435, USA

2 Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA

3 Program in Medical and Population Genetics, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA

4 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA

5 Department of Neurology, University Hospital Basel, CH 4031, Basel, Switzerland

6 Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam 1007 MB, The Netherlands

7 Florey Neuroscience Institutes, University of Melbourne, Victoria 3053, Australia

8 Department of Neurology, Yale University, New Haven, CT 06520-8018, USA

9 GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital and Department of Clinical Neurosciences, Imperial College, London W12 0NN, UK

10 Institute for Human Genetics, School of Medicine, University of California San Francisco, San Francisco, CA 94143-0435, USA

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Genome Medicine 2011, 3:3  doi:10.1186/gm217

Published: 18 January 2011

Abstract

Background

Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed.

Methods

We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool.

Results

In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years).

Conclusions

The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.