Genetic Overlap Between Multiple Sclerosis and Several Cardiovascular Disease Risk Factors
Total Page：16
File Type：pdf, Size：1020Kb
MSJ0010.1177/1352458516635873Multiple Sclerosis JournalY Wang, SD Bos 635873research-article2016 MULTIPLE SCLEROSIS MSJ JOURNAL Original Research Paper Multiple Sclerosis Journal Genetic overlap between multiple sclerosis and 2016, Vol. 22(14) 1783 –1793 DOI: 10.1177/ several cardiovascular disease risk factors 1352458516635873 © The Author(s), 2016. Reprints and permissions: Yunpeng Wang, Steffan D Bos, Hanne F Harbo, Wesley K Thompson, Andrew J Schork, http://www.sagepub.co.uk/ Francesco Bettella, Aree Witoelar, Benedicte A Lie, Wen Li, Linda K McEvoy, Srdjan Djurovic, journalsPermissions.nav Rahul S Desikan, Anders M Dale and Ole A Andreassen Abstract Background: Epidemiological findings suggest a relationship between multiple sclerosis (MS) and car- Correspondence to: diovascular disease (CVD) risk factors, although the nature of this relationship is not well understood. AM Dale Department of Radiology, Objective: We used genome-wide association study (GWAS) data to identify shared genetic factors University of California, San Diego, 8950 Villa La Jolla (pleiotropy) between MS and CVD risk factors. Drive, Suite C10, La Jolla, Methods: Using summary statistics from a large, recent GWAS (total n > 250,000 individuals), we inves- CA 92037-0841, USA. [email protected] tigated overlap in single nucleotide polymorphisms (SNPs) associated with MS and a number of CVD OA Andreassen risk factors including triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipopro- NORMENT, K.G. Jebsen Psychosis Research tein (HDL) cholesterol, body mass index, waist-to-hip ratio, type 2 diabetes, systolic blood pressure, and Centre, Institute of Clinical C-reactive protein level. Medicine, Oslo University Hospital and University of Results and conclusion: Using conditional enrichment plots, we found 30-fold enrichment of MS SNPs Oslo, Building 49, Ullevål, Kirkeveien 166, PO Box for different levels of association with LDL and TG SNPs, with a corresponding reduction in conditional 4956 Nydalen, 0424 Oslo, false discovery rate (FDR). We identified 133 pleiotropic loci outside the extended major histocompat- Norway. o.a.andreassen@medisin. ibility complex with conditional FDR < 0.01, of which 65 are novel. These pleiotropic loci were located uio.no on 21 different chromosomes. Our findings point to overlapping pathobiology between clinically diag- Yunpeng Wang NORMENT, K.G. Jebsen nosed MS and cardiovascular risk factors and identify novel common variants associated with increased Psychosis Research Centre, MS risk. Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway/Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Keywords: Multiple sclerosis, pleiotropy, gene discovery, cardiovascular risk factors Norway/Multimodal Imaging Laboratory, University of California, San Diego, La Date received: 17 September 2015; revised: 26 January 2016; accepted: 7 February 2016 Jolla, CA, USA/Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA Introduction have identified a total of 110 single nucleotide poly- Steffan D Bos Multiple sclerosis (MS) is an autoimmune disease morphisms (SNPs) associated with MS.5,6 Combining Hanne F Harbo Department of Neurology, characterized by demyelination of the central nervous GWAS from multiple disorders and phenotypes pro- Oslo University Hospital, system.1 A recent systematic review of six databases vides insights into genetic pleiotropy (defined as a sin- Ullevål, Oslo, Norway/ Institute of Clinical suggests that cardiovascular disease (CVD) risk is gle gene or variant being associated with more than Medicine, University of Oslo, increased among patients with MS.2 However, it is one distinct phenotype) and could elucidate shared Oslo, Norway unclear whether an increased CVD risk is secondary pathobiology. Using this approach, we have recently Wesley K Thompson Department of Psychiatry, to lifestyle and environmental variables, such as med- reported genetic overlap between a number of diseases University of California, San ication use, dietary factors, and physical activity, or and phenotypes and identified novel common variants Diego, La Jolla, CA, USA due to overlapping pathobiology between CVD risk associated with schizophrenia, bipolar disorder, pros- Andrew J Schork Multimodal Imaging factors and MS. tate cancer, hypertension, primary sclerosing chol- Laboratory, University of angitis, and Alzheimer’s disease.7–15 Here, taking California, San Diego, La Jolla, CA, USA/Cognitive Large genome-wide association studies (GWASs) advantage of several large GWASs, we evaluated Sciences Graduate Program, provide valuable insights into the role of biologic genetic overlap between MS and a number of CVD University of California, San Diego, La Jolla, CA, 16 pathways in disease pathogenesis and have identified risk factors, including systolic blood pressure (SBP), USA/Center for Human genetic polymorphisms associated with a range of low-density lipoprotein (LDL) cholesterol,17 high- Development, University of California, San Diego, La 3,4 17 human disorders and phenotypes. Recent GWAS density lipoprotein (HDL) cholesterol, triglycerides Jolla, CA, USA http://msj.sagepub.com 1783 Multiple Sclerosis Journal 22(14) Francesco Bettella 17 18 Aree Witoelar (TG), type 2 diabetes (T2D), body mass index To identify specific loci associated with MS, we com- Wen Li (BMI),19 waist-to-hip ratio (WHR),20 and C-reactive puted conditional False Discovery Rates (FDRs). The NORMENT, K.G. Jebsen 21 Psychosis Research protein (CRP) level. standard FDR framework is based on a mixture model Centre, Institute of Clinical of SNPs associated with the phenotype (either associ- Medicine, Oslo University ated; non-null SNPs, or not; null SNPs). The condi- Hospital and University of Oslo, Oslo, Norway/Division Materials and methods tional FDR is an extension of the standard FDR, of Mental Health and which incorporates information from GWAS sum- Addiction, Oslo University Hospital, Oslo, Norway Ethics statement mary statistics of a second phenotype. Specifically, Benedicte A Lie The relevant institutional review boards or ethics MS SNPs were stratified on the basis of p-values of Department of Medical Genetics, Oslo University committees approved the research protocol of the each of the CVD factors, separately. Then based on Hospital and University of individual GWAS used in the current analysis, and all the combination of p-values for SNPs in MS and each Oslo, Oslo, Norway human participants gave written informed consent. of the CVD factors, we assigned a conditional FDR Linda K McEvoy Multimodal Imaging value (FDRMS|CVD, CVD represent one of BMI, CRP, Laboratory, University of LDL, HDL, T2D, SBP, TG, and WHR) to each SNP California, San Diego, La Jolla, CA, USA/Department Participant samples for MS by interpolating into a two-dimensional (2D) of Radiology, University of We utilized summary statistics GWAS data (p-values lookup table (Supplementary Figure 1). We used a California–San Diego, La Jolla, CA, USA and odds ratios) from the International Multiple conditional FDR threshold of 0.01, which means 1 6 Srdjan Djurovic Sclerosis Genetics Consortium (IMSGC) (n = 27,148) false discovery per 100. Loci thus identified can be NORMENT, K.G. Jebsen and from GWAS evaluating SBP (n = 203,056),16 LDL visualized by a conditional Manhattan plot (Figure 2). Psychosis Research 17 17 17 Centre, Institute of Clinical (n = 188,577), HDL (n = 188,577), TG (n = 188,577), It is important to note that ranking SNPs by FDR or Medicine, Oslo University T2D (n = 22,044),18 BMI (n = 123,865),19 WHR by p-values both give the same ordering of SNPs, Hospital and University of 20 21 Oslo, Oslo, Norway/Division (n = 77,167) and CRP (n = 66,185) (for details, please whereas the conditional FDR re-orders SNPs result- of Mental Health and see Supplementary Table 1). All studies were approved ing in a different p-value based ranking if the primary Addiction, Oslo University Hospital, Oslo, Norway/ by the respective ethical committees and institutional and secondary phenotype are genetically related. Department of Medical review boards. Genetics, Oslo University Hospital and University of Low conditional FDR values can be driven by asso- Oslo, Oslo, Norway ciation with both phenotypes or with the primary phe- Rahul S Desikan Statistical analysis notype only. To detect true pleiotropic signal Department of Radiology and Biomedical Imaging, Using recently developed statistical methods to eval- (association with both phenotypes), we computed the University of California – uate pleiotropic effects,7–11 we evaluated genetic conjunctional FDR, computed as the maximum of the San Francisco, San Francisco, CA, USA overlap between MS and CVD risk factors. For given two conditional FDR values (i.e. MS conditional on Anders M Dale associated phenotypes A and B, pleiotropic “enrich- CVD factors and CVD risk factors conditional on NORMENT, K.G. Jebsen Psychosis Research ment” of phenotype A with phenotype B exists if the MS). Similar to conditional FDR, we assigned to each Centre, Institute of Clinical proportion of SNPs or genes associated with pheno- MS SNP a conjunctional FDR value using a 2D Medicine, Oslo University Hospital and University type A increases as a function of increased associa- lookup table (Supplementary Figure 2). We used of Oslo, Oslo, Norway/ tion with phenotype B (see Supplementary Text for overall a conjunctional FDR threshold of 0.05, which Department of Psychiatry,