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.
AlonsoAJickSSOlekMJHernanMA. 2007. Incidence of multiple sclerosis in the United Kingdom: findings from a population-based cohort. J Neurol254(12):1736–41.
2.
AlonsoALogroscinoGJickSSHernanMA. 2009. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol16(6):745–51.
3.
AmirREVan den VeyverIBWanMTranCQFranckeUZoghbiHY. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet23(2):185–8.
4.
AyrolesJFCarboneMAStoneEAJordanKWLymanRFMagwireMM, and others. 2009. Systems genetics of complex traits in Drosophila melanogaster. Nat Genet41(3):299–307.
5.
BaoAMSwaabDF. 2010. Sex differences in the brain, behavior, and neuropsychiatric disorders. Neuroscientist16(5):550–65.
6.
BerletchJBYangFXuJCarrelLDistecheCM. 2011. Genes that escape from X inactivation. Hum Genet130(2):237–45.
7.
BetarbetRShererTBMacKenzieGGarcia-OsunaMPanovAVGreenamyreJT. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci3(12):1301–6.
8.
BiedermanJMickEFaraoneSVBraatenEDoyleASpencerT, and others. 2002. Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic. Am J Psychiatry159(1):36–42.
9.
BoylesJKPitasREWilsonEMahleyRWTaylorJM. 1985. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest76(4):1501–13.
10.
BroeMKrilJHallidayGM. 2004. Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. Brain127(Pt 10):2214–20.
11.
BrunnerHGNelenMRVanzandvoortPAbelingNGGMVangennipAHWoltersEC, and others. 1993. X-linked borderline mental-retardation with prominent behavioral disturbance—phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet52(6):1032–9.
12.
CahillL. 2006. Why sex matters for neuroscience. Nat Rev Neurosci7(6):477–84.
13.
ChalmersRMDavisMBSweeneyMGWoodNWHardingAE. 1996. Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy. Am J Hum Genet59(1):103–8.
14.
ChenYSRaccaJDPhillipsNBWeissMA. 2013. Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold. Proc Natl Acad Sci U S A110(38):E3567–76.
15.
CohenILLiuXSchutzCWhiteBNJenkinsECBrownWT, and others. 2003. Association of autism severity with a monoamine oxidase A functional polymorphism. Clin Genet64(3):190–7.
16.
ComingsDEComingsBG. 1986. Evidence for an X-linked modifier gene affecting the expression of Tourette syndrome and its relevance to the increased frequency of speech, cognitive, and behavioral-disorders in males. Proc Natl Acad Sci U S A83(8):2551–5.
17.
CorderEHSaundersAMStrittmatterWJSchmechelDEGaskellPCSmallGW, and others. 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science261(5123):921–3.
18.
CrowTJ. 2013. The XY gene hypothesis of psychosis: origins and current status. Am J Med Genet B Neuropsychiatr Genet162(8):800–24.
19.
DavisLKHazlettHCLibrantALNopoulosPSheffieldVCPivenJ, and others. 2008. Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene. Am J Med Genet B Neuropsychiatr Genet147(7):1145–51.
20.
DengHGaoKJankovicJ. 2012. The genetics of Tourette syndrome. Nat Rev Neurol8(4):203–13.
21.
DicksonDWFeanyMBYenSHMattiaceLADaviesP. 1996. Cytoskeletal pathology in non-Alzheimer degenerative dementia: new lesions in diffuse Lewy body disease, Pick’s disease, and corticobasal degeneration. J Neural Transm Suppl47:31–46.
22.
Epidemiological Study of Dystonia in Europe Collaborative Group. 2000. A prevalence study of primary dystonia in eight European countries. J Neurol247(10):787–92.
23.
EvidenteVGH. 2005. X-linked dystonia-Parkinsonism. In: PagonRAAdamMPArdingerHHBirdTDDolanCRFongCT, and others, eds. GeneReviews. Seattle, WA: University of Washington, Seattle.
24.
GeorgesM. 2007. Mapping, fine mapping, and molecular dissection of quantitative trait loci in domestic animals. Annu Rev Genomics Hum Genet8:131–62.
25.
GilbertiNTurlaMAlbericiABertasiVCivelliPArchettiS, and others. 2012. Prevalence of frontotemporal lobar degeneration in an isolated population: the Vallecamonica study. Neurol Sci33(4):899–904.
26.
GillbergC. 1998. Chromosomal disorders and autism. J Autism Dev Disord28(5):415–25.
27.
GiordanoCMontopoliMPerliEOrlandiMFantinMRoss-CisnerosFN, and others. 2011. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain134:220–34.
28.
GiummoJJohnsonW. 2012. Testing for evidence of an X-linked genetic basis for a greater proportion of males with high cognitive ability. Behav Genet42(5):808–19.
29.
GizerIRFicksCWaldmanID. 2009. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet126(1):51–90.
30.
GoldsteinJMCherkerzianSSeidmanLJPetryshenTLFitzmauriceGTsuangMT, and others. 2011. Sex-specific rates of transmission of psychosis in the New England high-risk family study. Schizophr Res128(1–3):150–5.
31.
HaaxmaCABloemBRBormGFOyenWJLeendersKLEshuisS, and others. 2007. Gender differences in Parkinson’s disease. J Neurol Neurosurg Psychiatry78(8):819–24.
32.
HattoriMHashizumeYYoshidaMIwasakiYHishikawaNUedaR, and others. 2003. Distribution of astrocytic plaques in the corticobasal degeneration brain and comparison with tuft-shaped astrocytes in the progressive supranuclear palsy brain. Acta Neuropathol106(2):143–9.
33.
HoldenC. 2005. Sex and the suffering brain. Science308(5728):1574–7.
34.
HowesODKapurS. 2009. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull35(3):549–62.
35.
HuangWRichardsSCarboneMAZhuDAnholtRRAyrolesJF, and others. 2012. Epistasis dominates the genetic architecture of Drosophila quantitative traits. Proc Natl Acad Sci U S A109(39):15553–9.
36.
HudsonGKeersSManPYWGriffithsPHuoponenKSavontausML, and others. 2005. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet77(6):1086–91.
JacobAMcKeonANakashimaISatoDKElsoneLFujiharaK, and others. 2013. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry84(8):922–30.
39.
JacobJRobertsonNJHiltonDA. 2003. The clinicopathological spectrum of Rosenthal fibre encephalopathy and Alexander’s disease: a case report and review of the literature. J Neurol Neurosurg Psychiatry74(6):807–10.
40.
JamainSQuachHBetancurCRastamMColineauxCGillbergIC, and others. 2003. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet34(1):27–9.
41.
JariusSRuprechtKWildemannBKuempfelTRingelsteinMGeisC, and others. 2012. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation9:14.
42.
JiangZCowellRMNakazawaK. 2013. Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia. Front Behav Neurosci7:116.
43.
JohnsonWCarothersADearyIJ. 2009. A role for the X chromosome in sex differences in variability in general intelligence?Perspect Psychol Sci4(6):598–611.
44.
KomoriT. 1999. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol9(4):663–79.
45.
La SpadaARanumLPW. 2010. Molecular genetic advances in neurological disease: special review issue. Hum Mol Genet19(R1):R1–R3.
46.
LaheyBBApplegateBMcburnettKBiedermanJGreenhillLHyndGW, and others. 1994. DSM-IV field trials for attention-deficit hyperactivity disorder in children and adolescents. Am J Psychiatry151(11):1673–85.
47.
LaumonnierFCuthbertPCGrantSG. 2007. The role of neuronal complexes in human X-linked brain diseases. Am J Hum Genet80(2):205–20.
48.
Lawson-YuenASaldivarJSSommerSPickerJ. 2008. Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet16(5):614–8.
49.
LehrkeR. 1972. Theory of X-linkage of major intellectual traits. Am J Ment Defic76(6):611–9.
50.
LismanJECoyleJTGreenRWJavittDCBenesFMHeckersS, and others. 2008. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci31(5):234–42.
51.
LuqueJMKwanSWAbellCWDaPradaMRichardsJG. 1995. Cellular expression of mRNAs encoding monoamine oxidases A and B in the rat central nervous system. J Comp Neurol363(4):665–80.
52.
LyonsKEHubbleJPTrosterAIPahwaRKollerWC. 1998. Gender differences in Parkinson’s disease. Clin Neuropharmacol21(2):118–21.
53.
MarinO. 2012. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci13(2):107–20.
54.
McCombePAHendersonRD. 2010. Effects of gender in amyotrophic lateral sclerosis. Gend Med7(6):557–70.
55.
MeestersPDde HaanLComijsHCStekMLSmeets-JanssenMMJWeedaMR, and others. 2012. Schizophrenia spectrum disorders in later life: prevalence and distribution of age at onset and sex in a Dutch catchment area. Am J Geriatr Psychiatry20(1):18–28.
56.
MerrillRMLyonJLMatiacoPM. 2013. Tardive and spontaneous dyskinesia incidence in the general population. BMC Psychiatry13:152.
57.
MorrisonBEMarcondesMCNomuraDKSanchez-AlavezMSanchez-GonzalezASaarI, and others. 2012. Cutting edge: IL-13Ralpha1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic peripheral treatment with lipopolysaccharide. J Immunol189(12):5498–502.
58.
NasrallahHAMcCalley-WhittersMBigelowLBRauscherFP. 1983. A histological study of the corpus callosum in chronic schizophrenia. Psychiatry Res8(4):251–60.
59.
NathUBen-ShlomoYThomsonRGMorrisHRWoodNWLeesAJ, and others. 2001. The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK. Brain124(Pt 7):1438–49.
60.
NguyenDKDistecheCM. 2006. High expression of the mammalian X chromosome in brain. Brain Res1126(1):46–9.
61.
NisbettREAronsonJBlairCDickensWFlynnJHalpernDF, and others. 2012. Intelligence: new findings and theoretical developments. Am Psychol67(2):130–59.
62.
PankratzNNicholsWCUniackeSKHalterCMurrellJRudolphA, and others. 2003. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet12(20):2599–608.
63.
PankratzNNicholsWCUniackeSKHalterCRudolphAShultsC, and others. 2002. Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. Am J Hum Genet71(1):124–35.
64.
QuesseveurGDavidDJGaillardMCPlaPWuMVNguyenHT, and others. 2013. BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. Transl Psychiatry3:e253.
65.
RabinMLStevens-HaasCHavrillaEDeviTKurlanR. 2014. Movement disorders in women: a review. Mov Disord29(2):177–83.
66.
ReimanEMQuirozYTFleisherASChenKVelez-PardoCJimenez-Del-RioM, and others. 2012. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol11(12):1048–56.
RosenbergCKCummingsTJSaundersAMWidicoCMcIntyreLMHuletteCM. 2001. Dementia with Lewy bodies and Alzheimer’s disease. Acta Neuropathol102(6):621–6.
69.
RossMTGrafhamDVCoffeyAJSchererSMcLayKMuznyD, and others. 2005. The DNA sequence of the human X chromosome. Nature434(7031):325–37.
70.
ScottWKNanceMAWattsRLHubbleJPKollerWCLyonsK, and others. 2001. Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA286(18):2239–44.
71.
ShankarSPFingertJHCarelliVValentinoMLKingTMDaigerSP, and others. 2008. Evidence for a novel x-linked modifier locus for Leber hereditary optic neuropathy. Ophthalmic Genet29(1):17–24.
72.
StysPKZamponiGWvan MinnenJGeurtsJJ. 2012. Will the real multiple sclerosis please stand up?Nat Rev Neurosci13(7):507–14.
73.
SullivanPFKendlerKSNealeMC. 2003. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry60(12):1187–92.
74.
SullivanPFNealeMCKendlerKS. 2000. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry157(10):1552–62.
75.
SwanLDupontJ. 1999. Multiple system atrophy. Phys Ther79(5):488–94.
76.
SwansonJMSergeantJATaylorESonuga-BarkeEJJensenPSCantwellDP. 1998. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet351(9100):429–33.
77.
SwinglandJTDurrenbergerPFReynoldsRDexterDTPomboADeprezM, and others. 2012. Mean expression of the X chromosome is associated with neuronal density. Front Neurosci6:161.
78.
ThompsonAJPolmanCHMillerDHMcDonaldWIBrochetBFilippiMMX, and others. 1997. Primary progressive multiple sclerosis. Brain120(Pt 6):1085–96.
79.
TrabzuniDRamasamyAImranSWalkerRSmithCWealeME, and others. 2013. Widespread sex differences in gene expression and splicing in the adult human brain. Nat Commun4:2771.
80.
TrentSDaviesW. 2012. The influence of sex-linked genetic mechanisms on attention and impulsivity. Biol Psychol89(1):1–13.
81.
TurkheimerEHalpernDF. 2009. Sex differences in variability for cognitive measures: do the ends justify the genes? (Commentary on Johnson et al., 2009). Perspect Psychol Sci4(6):612–4.
82.
TurnerG. 1996. Intelligence and the X chromosome. Lancet347(9018):1814–5.
83.
TurnerGWebbTWakeSRobinsonH. 1996. Prevalence of fragile X syndrome. Am J Med Genet64(1):196–7.
84.
VikkiJOttJSavontausMLAulaPNikoskelainenEK. 1991. Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to Dxs7. Am J Hum Genet48(3):486–91.
85.
WatsonJBMednickSAHuttunenMWangX. 1999. Prenatal teratogens and the development of adult mental illness. Dev Psychopathol11(3):457–66.
86.
WenningGKColosimoCGeserFPoeweW. 2004. Multiple system atrophy. Lancet Neurol3(2):93–103.
87.
WuJBChenKLiYMLauYFCShihJC. 2009. Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. FASEB J23(11):4029–38.
88.
YassaRJesteDV. 1992. Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull18(4):701–15.
89.
YirmiyaR. 1996. Endotoxin produces a depressive-like episode in rats. Brain Res711(1–2):163–74.
90.
YooHJLeeSKParkMChoIHHyunSHLeeJC, and others. 2009. Family- and population-based association studies of monoamine oxidase A and autism spectrum disorders in Korean. Neurosci Res63(3):172–6.
91.
ZappiaMAnnesiGNicolettiGArabiaGAnnesiFMessinaD, and others. 2005. Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study. Arch Neurol62(4):601–5.
