Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci.
Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.
1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
O A
OA
Andreassen
Department of Neurology, Oslo University Hospital, Ullevål, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
H F
HF
Harbo
1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA [4] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Y
Y
Wang
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
W K
WK
Thompson
1] Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA [2] Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA [3] Center for Human Development, University of California at San Diego, La Jolla, CA, USA.
A J
AJ
Schork
1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Sørlandet Hospital, Kristiansand, Norway.
M
M
Mattingsdal
1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
V
V
Zuber
1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
F
F
Bettella
1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
S
S
Ripke
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
J R
JR
Kelsoe
Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
K S
KS
Kendler
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
M C
MC
O'Donovan
The Division of Psychiatric Genetics and Genomics, Mount Sinai School of Medicine, New York, NY, USA.
P
P
Sklar
1] Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA [2] Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
L K
LK
McEvoy
1] Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA [2] Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
R S
RS
Desikan
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
B A
BA
Lie
1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
S
S
Djurovic
1] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA [2] Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA [3] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA [4] Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
A M
AM
Dale
D001714:Bipolar Disorder / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*
D006680:HLA Antigens