A schizophrenia-associated HLA locus affects thalamus volume and asymmetry.
Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analysed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia.
Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; Leiden University Centre for Linguistics, Leiden, The Netherlands. Electronic address: n.g.a.brucato@hum.leidenuniv.nl.
Nicolas
N
Brucato
Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
Tulio
T
Guadalupe
Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Barbara
B
Franke
Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, The Netherlands.
Simon E
SE
Fisher
Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, The Netherlands.
Clyde
C
Francks
D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006624:Hippocampus / Q000033:anatomy & histology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics; D013788:Thalamus / Q000033:anatomy & histology*; D055815:Young Adult
D006680:HLA Antigens
Brain imaging genetics; HLA; Hippocampus; Laterality; MHC; Psychiatry; Thalamus