title: The X-Linked Hypothesis of Brain Disorders: Can Gender Ratios Tell Us Anything About Cellular Etiology of Neurodegenerative and Psychiatric Diseases?
abstract: In this article, we propose an X-linked hypothesis of brain disorders that postulates a neuronal origin of those neurodegenerative and psychiatric disorders with a greater male prevalence. The hypothesis is based on the accumulated genetics and genomic evidence linking X chromosome genes and transcripts to neuronal cells. The behavioral genetics literature has long pointed to the link between postsynaptic protein complexes coded on chromosome X and mental retardation. More recently, novel genomic evidence has emerged of X-linked mRNA overexpression of neuronal source in the human brain. We review the evidence for this hypothesis and its consistency with the distribution across genders of brain disorders of known aetiology. We then provide examples of the utilization of this hypothesis in the investigation of the pathophysiology of complex brain disorders in both the stratification of disease cohorts and the development of realistic preclinical models. We conclude by providing a general framework for testing its validity, which will be exploited in future studies, and provide future directions for research.
authors.affiliation: Institute of Psychiatry, King's College London, UK federico.turkheimer@kcl.ac.uk.
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.affiliation: Institute of Psychiatry, King's College London, UK Institut du Cerveau et de la Moelle épinière, Hôpital Pitié-Salpêtrière, UPMC, Paris, France.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bodini
authors.affiliation: Department of Clinical Neuroscience, King's College London, UK.
authors.forename: Marios
authors.initials: M
authors.lastname: Politis
authors.affiliation: Institute of Psychiatry, King's College London, UK.
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
authors.affiliation: Institute of Neurology, University College London, UK.
authors.forename: Olga
authors.initials: O
authors.lastname: Ciccarelli
authors.affiliation: Department of Psychology, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Yeo
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology; D001927:Brain Diseases / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000453:epidemiology / Q000503:physiopathology*; D006801:Humans; D001523:Mental Disorders / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D012737:Sex Factors
keywords: X chromosome; depression; gender ratio; neurodegeneration; neuron; schizophrenia