title: A common risk variant in CACNA1C supports a sex-dependent effect on longitudinal functioning and functional recovery from episodes of schizophrenia-spectrum but not bipolar disorder.
abstract: Sex is a powerful modulator of disease susceptibility, course and outcome. The gene CACNA1C is among the best replicated vulnerability genes of bipolar disorder and schizophrenia. The aim of the present study was to investigate whether sex and a variant in CACNA1C (rs10774035 as a proxy for the well-acknowledged risk variant rs1006737) influence psychosocial adaptation in a large German patient sample with schizophrenia-spectrum (n=297) and bipolar (n=516) disorders. We analyzed Global Assessment of Functioning (GAF) scores, retrospectively collected for different time points during disease course. We investigated whether CACNA1C sex-dependently modulates longitudinal GAF scores and recovery from episodes of psychiatric disturbance in the above mentioned disorders. Psychosocial recovery was measured as difference score between the current GAF score (assessing the last remission) and the worst GAF score ever during an illness episode. Covariate- adjusted association analyses revealed a sex × rs10774035 genotype interaction on longitudinal GAF and recovery from illness episodes only in schizophrenia-spectrum but not in bipolar disorders. In schizophrenia-spectrum affected males, rs10774035 minor allele (T) carriers had higher GAF scores at three time points (premorbid, worst ever, current). In contrast, females carrying rs10774035 minor alleles had impaired recovery from schizophrenia-spectrum episodes. These results encourage further investigations of gene × sex interactions and longitudinal quantitative phenotypes to unravel the rich variety of behavioral consequences of genetic individuality.
authors.affiliation: Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Germany. Electronic address: urs.heilbronner@med.uni-muenchen.de.
authors.forename: Urs
authors.initials: U
authors.lastname: Heilbronner
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany.
authors.forename: Dörthe
authors.initials: D
authors.lastname: Malzahn
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Maier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Treutlein
authors.affiliation: Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich (FZJ), Jülich, Germany; Institute of Human Genetics, University of Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany; Division of Medical Genetics, University Hospital Basel, University of Basel, Switzerland; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Falkai
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Germany; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany; Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors; D055815:Young Adult
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: Calcium channel; GAF; GAS; Global assessment of functioning; Recovery; Schizoaffective