title: Schizophrenia risk variants modulate white matter volume across the psychosis spectrum: evidence from two independent cohorts.
abstract: Polygenic risk scores, based on risk variants identified in genome-wide-association-studies (GWAS), explain a considerable portion of the heritability for schizophrenia (SZ) and bipolar disorder (BD). However, little is known about the combined effects of these variants, although polygenic neuroimaging has developed into a powerful tool of translational neuroscience. In this study, we used genome wide significant SZ risk variants to test the predictive capacity of the polygenic model and explored potential associations with white matter volume, a key candidate in imaging phenotype for psychotic disorders. By calculating the combined additive schizophrenia risk of seven SNPs (significant hits from a recent schizophrenia GWAS study), we show that increased additive genetic risk for SZ was associated with reduced white matter volume in a group of participants (n = 94) consisting of healthy individuals, SZ first-degree relatives, SZ patients and BD patients. This effect was also seen in a second independent sample of healthy individuals (n = 89). We suggest that a moderate portion of variance (~4%) of white matter volume can be explained by the seven hits from the recent schizophrenia GWAS. These results provide evidence for associations between cumulative genetic risk for schizophrenia and intermediate neuroimaging phenotypes in models of psychosis. Our work contributes to a growing body of literature suggesting that polygenic risk may help to explain white matter alterations associated with familial risk for psychosis.
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Oertel-Knöchel
authors.affiliation: Neuroscience and Mental Health Research Institute and MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Lancaster
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Knöchel
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stäblein
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Storchak
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Reinke
authors.affiliation: Institute for Neuroradiology, Goethe Univ., Frankfurt a. M, Germany ; Center for Individual Development and Adaptive Education of Children at Risk, Frankfurt, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Jurcoane
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kniep
authors.affiliation: Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Neuroimaging, Goethe Univ., Frankfurt a. M, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Prvulovic
authors.affiliation: Neuroscience and Mental Health Research Institute and MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: Neuroscience and Mental Health Research Institute and MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.affiliation: Neuroscience and Mental Health Research Institute and MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Neuroscience and Mental Health Research Institute and MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Neuroscience and Mental Health Research Institute and MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: David E J
authors.initials: DE
authors.lastname: Linden
mesh_terms: D000368:Aged; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics / Q000473:pathology*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D066127:White Matter / Q000473:pathology*
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