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Rethinking the genetic architecture of schizophrenia

  • K. J. Mitchell (a1) and D. J. Porteous (a2)
  • DOI: http://dx.doi.org/10.1017/S003329171000070X
  • Published online: 12 April 2010
Abstract
Background

For many years, the prevailing paradigm has stated that in each individual with schizophrenia (SZ) the genetic risk is due to a combination of many genetic variants, individually of small effect. Recent empirical data are prompting a re-evaluation of this polygenic, common disease–common variant (CDCV) model. Evidence includes a lack of the expected strong positive findings from genome-wide association studies and the concurrent discovery of many different mutations that individually strongly predispose to SZ and other psychiatric disorders. This has led some to adopt a mixed model wherein some cases are caused by polygenic mechanisms and some by single mutations. This model runs counter to a substantial body of theoretical literature that had supposedly conclusively rejected Mendelian inheritance with genetic heterogeneity. Here we ask how this discrepancy between theory and data arose and propose a rationalization of the recent evidence base.

Method

In light of recent empirical findings, we reconsider the methods and conclusions of early theoretical analyses and the explicit assumptions underlying them.

Results

We show that many of these assumptions can now be seen to be false and that the model of genetic heterogeneity is consistent with observed familial recurrence risks, endophenotype studies and other population-wide parameters.

Conclusions

We argue for a more biologically consilient mixed model that involves interactions between disease-causing and disease-modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms.

Copyright
Corresponding author
*Address for correspondence: Dr K. J. Mitchell, Smurfit Institute of Genetics, Trinity College Dublin, Ireland. (Email: Kevin.Mitchell@tcd.ie)
(Email: David.Porteous@ed.ac.uk)
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

B Bakkaloglu , BJ O'Roak , A Louvi , AR Gupta , JF Abelson , TM Morgan , K Chawarska , A Klin , AG Ercan-Sencicek , AA Stillman , G Tanriover , BS Abrahams , JA Duvall , EM Robbins , DH Geschwind , T Biederer , M Gunel , RP Lifton , MW State (2008). Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. American Journal of Human Genetics 82, 165173.

BC Ballif , A Theisen , J Coppinger , GC Gowans , JH Hersh , S Madan-Khetarpal , KR Schmidt , R Tervo , LF Escobar , CA Friedrich , M McDonald , L Campbell , JE Ming , EH Zackai , BA Bejjani , LG Shaffer (2008). Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Molecular Cytogenetics 1, 8.

JH Barnett , CH Salmond , PB Jones , BJ Sahakian (2006). Cognitive reserve in neuropsychiatry. Psychological Medicine 36, 10531064.

DH Blackwood , WJ Muir (2004). Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotoxicity Research 6, 3541.

DL Braff , R Freedman , NJ Schork , II Gottesman (2007). Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophrenia Bulletin 33, 2132.

N Brunetti-Pierri , JS Berg , F Scaglia , J Belmont , CA Bacino , T Sahoo , SR Lalani , B Graham , B Lee , M Shinawi , J Shen , SH Kang , A Pursley , T Lotze , G Kennedy , S Lansky-Shafer , C Weaver , ER Roeder , TA Grebe , GL Arnold , T Hutchison , T Reimschisel , S Amato , MT Geragthy , JW Innis , E Obersztyn , B Nowakowska , SS Rosengren , PI Bader , DK Grange , S Naqvi , AD Garnica , SM Bernes , CT Fong , A Summers , WD Walters , JR Lupski , P Stankiewicz , SW Cheung , A Patel (2008). Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics 40, 14661471.

M Bucan , BS Abrahams , K Wang , JT Glessner , EI Herman , LI Sonnenblick , AI Alvarez Retuerto , M Imielinski , D Hadley , JP Bradfield , C Kim , NB Gidaya , I Lindquist , T Hutman , M Sigman , V Kustanovich , CM Lajonchere , A Singleton , J Kim , TH Wassink , WM McMahon , T Owley , JA Sweeney , H Coon , JI Nurnberger , M Li , RM Cantor , NJ Minshew , JS Sutcliffe , EH Cook , G Dawson , JD Buxbaum , SF Grant , GD Schellenberg , DH Geschwind , H Hakonarson (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics 5, e1000536.

AG Cardno , FV Rijsdijk , PC Sham , RM Murray , P McGuffin (2002). A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 159, 539545.

WT Carpenter , JI Koenig (2008). The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 33, 20612079.

MC Cheng , CH Chen (2007). Identification of rare mutations of synaptogyrin 1 gene in patients with schizophrenia. Journal of Psychiatric Research 41, 10271031.

JE Chubb , NJ Bradshaw , DC Soares , DJ Porteous , JK Millar (2008). The DISC locus in psychiatric illness. Molecular Psychiatry 13, 3664.

JC Cohen , RS Kiss , A Pertsemlidis , YL Marcel , R McPherson , HH Hobbs (2004). Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869872.

JF Crow (2000). The origins, patterns and implications of human spontaneous mutation. Nature Reviews Genetics 1, 4047.

L Erlenmeyer-Kimling , D Rock , SA Roberts , M Janal , C Kestenbaum , B Cornblatt , UH Adamo , II Gottesman (2000). Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project. American Journal of Psychiatry 157, 14161422.

KA Frazer , SS Murray , NJ Schork , EJ Topol (2009). Human genetic variation and its contribution to complex traits. Nature Reviews Genetics 10, 241251.

JI Friedman , T Vrijenhoek , S Markx , IM Janssen , WA van der Vliet , BH Faas , NV Knoers , W Cahn , RS Kahn , L Edelmann , KL Davis , JM Silverman , HG Brunner , AG van Kessel , C Wijmenga , RA Ophoff , JA Veltman (2008). CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Molecular Psychiatry 13, 261266.

M Funayama , Y Li , TH Tsoi , CW Lam , T Ohi , S Yazawa , E Uyama , R Djaldetti , E Melamed , H Yoshino , Y Imamichi , H Takashima , K Nishioka , K Sato , H Tomiyama , S Kubo , Y Mizuno , N Hattori (2008). Familial Parkinsonism with digenic parkin and PINK1 mutations. Movement Disorders 23, 14611465.

S Girirajan , JA Rosenfeld , GM Cooper , F Antonacci , P Siswara , A Itsara , L Vives , T Walsh , SE McCarthy , C Baker , HC Mefford , JM Kidd , SR Browning , BL Browning , DE Dickel , DL Levy , BC Ballif , K Platky , DM Farber , GC Gowans , JJ Wetherbee , A Asamoah , DD Weaver , PR Mark , J Dickerson , BP Garg , SA Ellingwood , R Smith , VC Banks , W Smith , MT McDonald , JJ Hoo , BN French , C Hudson , JP Johnson , JR Ozmore , JB Moeschler , U Surti , LF Escobar , D El-Khechen , JL Gorski , J Kussmann , B Salbert , Y Lacassie , A Biser , DM McDonald-McGinn , EH Zackai , MA Deardorff , TH Shaikh , E Haan , KL Friend , M Fichera , C Romano , J Gecz , LE DeLisi , J Sebat , MC King , LG Shaffer , EE Eichler (2010). A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics 42, 203209.

JT Glessner , K Wang , G Cai , O Korvatska , CE Kim , S Wood , H Zhang , A Estes , CW Brune , JP Bradfield , M Imielinski , EC Frackelton , J Reichert , EL Crawford , J Munson , PM Sleiman , R Chiavacci , K Annaiah , K Thomas , C Hou , W Glaberson , J Flory , F Otieno , M Garris , L Soorya , L Klei , J Piven , KJ Meyer , E Anagnostou , T Sakurai , RM Game , DS Rudd , D Zurawiecki , CJ McDougle , LK Davis , J Miller , DJ Posey , S Michaels , A Kolevzon , JM Silverman , R Bernier , SE Levy , RT Schultz , G Dawson , T Owley , WM McMahon , TH Wassink , JA Sweeney , JI Nurnberger , H Coon , JS Sutcliffe , NJ Minshew , SF Grant , M Bucan , EH Cook , JD Buxbaum , B Devlin , GD Schellenberg , H Hakonarson (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569573.

DB Goldstein (2009). Common genetic variation and human traits. New England Journal of Medicine 360, 16961698.

II Gottesman , TD Gould (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636645.

II Gottesman , TM Laursen , A Bertelsen , PB Mortensen (2010). Severe mental disorders in offspring with 2 psychiatrically ill parents. Archives of General Psychiatry 67, 252257.

II Gottesman , J Shields (1967). A polygenic theory of schizophrenia. Proceedings of the National Academy of Sciences USA 58, 199205.

I Gregory (1960). Genetic factors in schizophrenia. American Journal of Psychiatry 116, 961972.

A Guilmatre , C Dubourg , AL Mosca , S Legallic , A Goldenberg , V Drouin-Garraud , V Layet , A Rosier , S Briault , F Bonnet-Brilhault , F Laumonnier , S Odent , G Le Vacon , G Joly-Helas , V David , C Bendavid , JM Pinoit , C Henry , C Impallomeni , E Germano , G Tortorella , G Di Rosa , C Barthelemy , C Andres , L Faivre , T Frebourg , P Saugier Veber , D Campion (2009). Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Archives of General Psychiatry 66, 947956.

FD Hannes , AJ Sharp , HC Mefford , T de Ravel , CA Ruivenkamp , MH Breuning , JP Fryns , K Devriendt , G Van Buggenhout , A Vogels , H Stewart , RC Hennekam , GM Cooper , R Regan , SJ Knight , EE Eichler , JR Vermeesch (2009). Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. Journal of Medical Genetics 46, 223232.

International Schizophrenia Consortium (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237241.

JW James (1971). Frequency in relatives for an all-or-none trait. Annals of Human Genetics 35, 4749.

W Ji , JN Foo , BJ O'Roak , H Zhao , MG Larson , DB Simon , C Newton-Cheh , MW State , D Levy , RP Lifton (2008). Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature Genetics 40, 592599.

A Kamiya , PL Tan , K Kubo , C Engelhard , K Ishizuka , A Kubo , S Tsukita , AE Pulver , K Nakajima , NG Cascella , N Katsanis , A Sawa (2008). Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Archives of General Psychiatry 65, 996–1006.

MC Keller , G Miller (2006). Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behavioral and Brain Sciences 29, 385404; discussion 405–452.

KS Kendler , KK Kidd (1986). Recurrence risks in an oligogenic threshold model: the effect of alterations in allele frequency. Annals of Human Genetics 50, 8391.

M Kerszberg (2004). Noise, delays, robustness, canalization and all that. Current Opinion in Genetics and Development 14, 440445.

DK Kinney , P Teixeira , D Hsu , SC Napoleon , DJ Crowley , A Miller , W Hyman , E Huang (2009). Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: a role for prenatal vitamin D deficiency and infections? Schizophrenia Bulletin 35, 582595.

G Kirov , D Grozeva , N Norton , D Ivanov , KK Mantripragada , P Holmans , N Craddock , MJ Owen , MC O'Donovan (2009). Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Human Molecular Genetics 18, 14971503.

G Kirov , D Gumus , W Chen , N Norton , L Georgieva , M Sari , MC O'Donovan , F Erdogan , MJ Owen , HH Ropers , R Ullmann (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Human Molecular Genetics 17, 458465.

H Kitano (2004). Biological robustness. Nature Reviews Genetics 5, 826837.

HM Knight , BS Pickard , A Maclean , MP Malloy , DC Soares , AF McRae , A Condie , A White , W Hawkins , K McGhee , M van Beck , DJ Macintyre , JM Starr , IJ Deary , PM Visscher , DJ Porteous , RE Cannon , D St Clair , WJ Muir , DH Blackwood (2009). A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. American Journal of Human Genetics 85, 833846.

GV Kryukov , LA Pennacchio , SR Sunyaev (2007). Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. American Journal of Human Genetics 80, 727739.

P Lichtenstein , BH Yip , C Bjork , Y Pawitan , TD Cannon , PF Sullivan , CM Hultman (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234239.

JR Lupski (2007). Genomic rearrangements and sporadic disease. Nature Genetics 39, S43S47.

S Mah , MR Nelson , LE Delisi , RH Reneland , N Markward , MR James , DR Nyholt , N Hayward , H Handoko , B Mowry , S Kammerer , A Braun (2006). Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Molecular Psychiatry 11, 471478.

D Malaspina , S Harlap , S Fennig , D Heiman , D Nahon , D Feldman , ES Susser (2001). Advancing paternal age and the risk of schizophrenia. Archives of General Psychiatry 58, 361367.

CR Marshall , A Noor , JB Vincent , AC Lionel , L Feuk , J Skaug , M Shago , R Moessner , D Pinto , Y Ren , B Thiruvahindrapduram , A Fiebig , S Schreiber , J Friedman , CE Ketelaars , YJ Vos , C Ficicioglu , S Kirkpatrick , R Nicolson , L Sloman , A Summers , CA Gibbons , A Teebi , D Chitayat , R Weksberg , A Thompson , C Vardy , V Crosbie , S Luscombe , R Baatjes , L Zwaigenbaum , W Roberts , B Fernandez , P Szatmari , SW Scherer (2008). Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics 82, 477488.

JM McClellan , E Susser , MC King (2007). Schizophrenia: a common disease caused by multiple rare alleles. British Journal of Psychiatry 190, 194199.

M McGue , II Gottesman , DC Rao (1985). Resolving genetic models for the transmission of schizophrenia. Genetic Epidemiology 2, 99–110.

HC Mefford , GM Cooper , T Zerr , JD Smith , C Baker , N Shafer , EC Thorland , C Skinner , CE Schwartz , DA Nickerson , EE Eichler (2009). A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Research 19, 15791585.

HC Mefford , AJ Sharp , C Baker , A Itsara , Z Jiang , K Buysse , S Huang , VK Maloney , JA Crolla , D Baralle , A Collins , C Mercer , K Norga , T de Ravel , K Devriendt , EM Bongers , N de Leeuw , W Reardon , S Gimelli , F Bena , RC Hennekam , A Male , L Gaunt , J Clayton-Smith , I Simonic , SM Park , SG Mehta , S Nik-Zainal , CG Woods , HV Firth , G Parkin , M Fichera , S Reitano , M Lo Giudice , KE Li , I Casuga , A Broomer , B Conrad , M Schwerzmann , L Raber , S Gallati , P Striano , A Coppola , JL Tolmie , ES Tobias , C Lilley , L Armengol , Y Spysschaert , P Verloo , A De Coene , L Goossens , G Mortier , F Speleman , E van Binsbergen , MR Nelen , R Hochstenbach , M Poot , L Gallagher , M Gill , J McClellan , MC King , R Regan , C Skinner , RE Stevenson , SE Antonarakis , C Chen , X Estivill , B Menten , G Gimelli , S Gribble , S Schwartz , JS Sutcliffe , T Walsh , SJ Knight , J Sebat , C Romano , CE Schwartz , JA Veltman , BB de Vries , JR Vermeesch , JC Barber , L Willatt , M Tassabehji , EE Eichler (2008). Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359, 16851699.

KR Merikangas (1982). Assortative mating for psychiatric disorders and psychological traits. Archives of General Psychiatry 39, 11731180.

JK Millar , BS Pickard , S Mackie , R James , S Christie , SR Buchanan , MP Malloy , JE Chubb , E Huston , GS Baillie , PA Thomson , EV Hill , NJ Brandon , JC Rain , LM Camargo , PJ Whiting , MD Houslay , DH Blackwood , WJ Muir , DJ Porteous (2005). DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310, 11871191.

JK Millar , JC Wilson-Annan , S Anderson , S Christie , MS Taylor , CA Semple , RS Devon , DM Clair , WJ Muir , DH Blackwood , DJ Porteous (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics 9, 14151423.

DT Miller , Y Shen , LA Weiss , J Korn , I Anselm , C Bridgemohan , GF Cox , H Dickinson , J Gentile , DJ Harris , V Hegde , R Hundley , O Khwaja , S Kothare , C Luedke , R Nasir , A Poduri , K Prasad , P Raffalli , A Reinhard , SE Smith , MM Sobeih , JS Soul , J Stoler , M Takeoka , WH Tan , J Thakuria , R Wolff , R Yusupov , JF Gusella , MJ Daly , BL Wu (2009). Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. Journal of Medical Genetics 46, 242248.

KJ Mitchell (2007). The genetics of brain wiring: from molecule to mind. PLoS Biology 5, e113.

JH Nadeau (2001). Modifier genes in mice and humans. Nature Reviews Genetics 2, 165174.

AC Need , D Ge , ME Weale , J Maia , S Feng , EL Heinzen , KV Shianna , W Yoon , D Kasperaviciute , M Gennarelli , WJ Strittmatter , C Bonvicini , G Rossi , K Jayathilake , PA Cola , JP McEvoy , RS Keefe , EM Fisher , PL St Jean , I Giegling , AM Hartmann , HJ Moller , A Ruppert , G Fraser , C Crombie , LT Middleton , D St Clair , AD Roses , P Muglia , C Francks , D Rujescu , HY Meltzer , DB Goldstein (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics 5, e1000373.

PC Ng , S Levy , J Huang , TB Stockwell , BP Walenz , K Li , N Axelrod , DA Busam , RL Strausberg , JC Venter (2008). Genetic variation in an individual human exome. PLoS Genetics 4, e1000160.

MC O'Donovan , N Craddock , N Norton , H Williams , T Peirce , V Moskvina , I Nikolov , M Hamshere , L Carroll , L Georgieva , S Dwyer , P Holmans , JL Marchini , CC Spencer , B Howie , HT Leung , AM Hartmann , HJ Moller , DW Morris , Y Shi , G Feng , P Hoffmann , P Propping , C Vasilescu , W Maier , M Rietschel , S Zammit , J Schumacher , EM Quinn , TG Schulze , NM Williams , I Giegling , N Iwata , M Ikeda , A Darvasi , S Shifman , L He , J Duan , AR Sanders , DF Levinson , PV Gejman , S Cichon , MM Nothen , M Gill , A Corvin , D Rujescu , G Kirov , MJ Owen , NG Buccola , BJ Mowry , R Freedman , F Amin , DW Black , JM Silverman , WF Byerley , CR Cloninger (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics 40, 10531055.

DG Owens , EC Johnstone (2006). Precursors and prodromata of schizophrenia: findings from the Edinburgh High Risk Study and their literature context. Psychological Medicine 36, 15011514.

JP Park , JB Moeschler , SZ Berg , DH Wurster-Hill (1991). Schizophrenia and mental retardation in an adult male with a de novo interstitial deletion 9(q32q34.1). Journal of Medical Genetics 28, 282283.

BS Pickard , EJ Hollox , MP Malloy , DJ Porteous , DH Blackwood , JA Armour , WJ Muir (2004). A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation. BMC Medical Genetics 5, 21.

BS Pickard , MP Malloy , A Christoforou , PA Thomson , KL Evans , SW Morris , M Hampson , DJ Porteous , DH Blackwood , WJ Muir (2006). Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Molecular Psychiatry 11, 847857.

BS Pickard , MP Malloy , DJ Porteous , DH Blackwood , WJ Muir (2005). Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 136B, 2632.

D Porteous (2008). Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. Current Opinion in Genetics and Development 18, 229234.

KM Prasad , R Sanders , J Sweeney , D Montrose , V Diwadkar , D Dworakowski , J Miewald , M Keshavan (2009). Neurological abnormalities among offspring of persons with schizophrenia: relation to premorbid psychopathology. Schizophrenia Research 108, 163169.

Psychiatric GWAS Consortium Steering Committee (2009). A framework for interpreting genome-wide association studies of psychiatric disorders. Molecular Psychiatry 14, 1017.

P Qin , H Xu , TM Laursen , M Vestergaard , PB Mortensen (2005). Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. British Medical Journal 331, 23.

S Raychaudhuri , RM Plenge , EJ Rossin , AC Ng , SM Purcell , P Sklar , EM Scolnick , RJ Xavier , D Altshuler , MJ Daly (2009). Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genetics 5, e1000534.

DE Reich , ES Lander (2001). On the allelic spectrum of human disease. Trends in Genetics 17, 502510.

N Risch (1990 a). Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genetic Epidemiology 7, 3–16; discussion 17–45.

N Risch , K Merikangas (1996). The future of genetic studies of complex human diseases. Science 273, 15161517.

AM Saperstein , RL Fuller , MT Avila , H Adami , RP McMahon , GK Thaker , JM Gold (2006). Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction. Schizophrenia Bulletin 32, 498506.

J Sebat , B Lakshmi , J Troge , J Alexander , J Young , P Lundin , S Maner , H Massa , M Walker , M Chi , N Navin , R Lucito , J Healy , J Hicks , K Ye , A Reiner , TC Gilliam , B Trask , N Patterson , A Zetterberg , M Wigler (2004). Large-scale copy number polymorphism in the human genome. Science 305, 525528.

J Sebat , DL Levy , SE McCarthy (2009). Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends in Genetics 25, 528535.

H Shao , LC Burrage , DS Sinasac , AE Hill , SR Ernest , W O'Brien , HW Courtland , KJ Jepsen , A Kirby , EJ Kulbokas , MJ Daly , KW Broman , ES Lander , JH Nadeau (2008). Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proceedings of the National Academy of Sciences USA 105, 1991019914.

YY Shi , G He , Z Zhang , W Tang , Jr. J Zhang , Q Zhao , Sr. J Zhang , XW Li , ZR Xi , C Fang , XZ Zhao , GY Feng , L He (2008). A study of rare structural variants in schizophrenia patients and normal controls from Chinese Han population. Molecular Psychiatry 13, 911913.

ML Siegal , A Bergman (2002). Waddington's canalization revisited: developmental stability and evolution. Proceedings of the National Academy of Sciences USA 99, 1052810532.

W Song , W Li , J Feng , LL Heston , WA Scaringe , SS Sommer (2008). Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochemical and Biophysical Research Communications 367, 700706.

H Stefansson , D Rujescu , S Cichon , OP Pietilainen , A Ingason , S Steinberg , R Fossdal , E Sigurdsson , T Sigmundsson , JE Buizer-Voskamp , T Hansen , KD Jakobsen , P Muglia , C Francks , PM Matthews , A Gylfason , BV Halldorsson , D Gudbjartsson , TE Thorgeirsson , A Sigurdsson , A Jonasdottir , A Bjornsson , S Mattiasdottir , T Blondal , M Haraldsson , BB Magnusdottir , I Giegling , HJ Moller , A Hartmann , KV Shianna , D Ge , AC Need , C Crombie , G Fraser , N Walker , J Lonnqvist , J Suvisaari , A Tuulio-Henriksson , T Paunio , T Toulopoulou , E Bramon , M Di Forti , R Murray , M Ruggeri , E Vassos , S Tosato , M Walshe , T Li , C Vasilescu , TW Muhleisen , AG Wang , H Ullum , S Djurovic , I Melle , J Olesen , LA Kiemeney , B Franke , C Sabatti , NB Freimer , JR Gulcher , U Thorsteinsdottir , A Kong , OA Andreassen , RA Ophoff , A Georgi , M Rietschel , T Werge , H Petursson , DB Goldstein , MM Nothen , L Peltonen , DA Collier , D St Clair , K Stefansson (2008). Large recurrent microdeletions associated with schizophrenia. Nature 455, 232236.

HC Steinhausen , L Foldager , G Perto , P Munk-Jorgensen (2009). Family aggregation of mental disorders in the nationwide Danish three generation study. European Archives of Psychiatry and Clinical Neuroscience 259, 270277.

S Steinlechner , J Stahlberg , B Volkel , A Djarmati , J Hagenah , A Hiller , K Hedrich , I Konig , C Klein , R Lencer (2007). Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations. Journal of Neurology, Neurosurgery, and Psychiatry 78, 532535.

R Tandon , MS Keshavan , HA Nasrallah (2008). Schizophrenia, ‘just the facts’ what we know in 2008. 2. Epidemiology and etiology. Schizophrenia Research 102, 118.

MT Tsuang , KD Bucher , JA Fleming (1982). Testing the monogenic theory of schizophrenia: an application of segregation analysis to blind family study data. British Journal of Psychiatry 140, 595599.

BI Turetsky , TA Greenwood , A Olincy , AD Radant , DL Braff , KS Cadenhead , DJ Dobie , R Freedman , MF Green , RE Gur , RC Gur , GA Light , J Mintz , KH Nuechterlein , NJ Schork , LJ Seidman , LJ Siever , JM Silverman , WS Stone , NR Swerdlow , DW Tsuang , MT Tsuang , ME Calkins (2008). Abnormal auditory N100 amplitude: a heritable endophenotype in first-degree relatives of schizophrenia probands. Biological Psychiatry 64, 10511059.

BW van Bon , HC Mefford , B Menten , DA Koolen , AJ Sharp , WM Nillesen , JW Innis , TJ de Ravel , CL Mercer , M Fichera , H Stewart , LE Connell , K Ounap , K Lachlan , B Castle , N Van der Aa , C van Ravenswaaij , MA Nobrega , C Serra-Juhe , I Simonic , N de Leeuw , R Pfundt , EM Bongers , C Baker , P Finnemore , S Huang , VK Maloney , JA Crolla , M van Kalmthout , M Elia , G Vandeweyer , JP Fryns , S Janssens , N Foulds , S Reitano , K Smith , S Parkel , B Loeys , CG Woods , A Oostra , F Speleman , AC Pereira , A Kurg , L Willatt , SJ Knight , JR Vermeesch , C Romano , JC Barber , G Mortier , LA Perez-Jurado , F Kooy , HG Brunner , EE Eichler , T Kleefstra , BB de Vries (2009). Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. Journal of Medical Genetics 46, 511523.

AJ Verkerk , CA Mathews , M Joosse , BH Eussen , P Heutink , BA Oostra (2003). CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82, 19.

R Verma , C Chauhan , Q Saleem , C Gandhi , S Jain , SK Brahmachari (2004). A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia. Biological Psychiatry 55, 196199.

T Vrijenhoek , JE Buizer-Voskamp , I van der Stelt , E Strengman , C Sabatti , A Geurts van Kessel , HG Brunner , RA Ophoff , JA Veltman (2008). Recurrent CNVs disrupt three candidate genes in schizophrenia patients. American Journal of Human Genetics 83, 504510.

CH Waddington (1959). Canalization of development and genetic assimilation of acquired characters. Nature 183, 16541655.

JL Waddington , AP Corvin , G Donohoe , CM O'Tuathaigh , KJ Mitchell , M Gill (2007). Functional genomics and schizophrenia: endophenotypes and mutant models. Psychiatric Clinics of North America 30, 365399.

T Walsh , JM McClellan , SE McCarthy , AM Addington , SB Pierce , GM Cooper , AS Nord , M Kusenda , D Malhotra , A Bhandari , SM Stray , CF Rippey , P Roccanova , V Makarov , B Lakshmi , RL Findling , L Sikich , T Stromberg , B Merriman , N Gogtay , P Butler , K Eckstrand , L Noory , P Gochman , R Long , Z Chen , S Davis , C Baker , EE Eichler , PS Meltzer , SF Nelson , AB Singleton , MK Lee , JL Rapoport , MC King , J Sebat (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539543.

LA Weiss , Y Shen , JM Korn , DE Arking , DT Miller , R Fossdal , E Saemundsen , H Stefansson , MA Ferreira , T Green , OS Platt , DM Ruderfer , CA Walsh , D Altshuler , A Chakravarti , RE Tanzi , K Stefansson , SL Santangelo , JF Gusella , P Sklar , BL Wu , MJ Daly (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667675.

DA Wheeler , M Srinivasan , M Egholm , Y Shen , L Chen , A McGuire , W He , YJ Chen , V Makhijani , GT Roth , X Gomes , K Tartaro , F Niazi , CL Turcotte , GP Irzyk , JR Lupski , C Chinault , XZ Song , Y Liu , Y Yuan , L Nazareth , X Qin , DM Muzny , M Margulies , GM Weinstock , RA Gibbs , JM Rothberg (2008). The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872876.

M Wohl , P Gorwood (2007). Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring. European Psychiatry 22, 2226.

KA Woodberry , AJ Giuliano , LJ Seidman (2008). Premorbid IQ in schizophrenia: a meta-analytic review. American Journal of Psychiatry 165, 579587.

CM Woolf (1997). Does the genotype for schizophrenia often remain unexpressed because of canalization and stochastic events during development? Psychological Medicine 27, 659668.

B Xu , JL Roos , S Levy , EJ van Rensburg , JA Gogos , M Karayiorgou (2008). Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genetics 40, 880885.

B Xu , A Woodroffe , L Rodriguez-Murillo , JL Roos , EJ van Rensburg , GR Abecasis , JA Gogos , M Karayiorgou (2009). Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans. Proceedings of the National Academy of Sciences USA 106, 1674616751.

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Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
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