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Articles   |    
Genome-Wide Linkage Analyses of 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia
Tiffany A. Greenwood, Ph.D.; Neal R. Swerdlow, M.D., Ph.D.; Raquel E. Gur, M.D., Ph.D.; Kristin S. Cadenhead, M.D.; Monica E. Calkins, Ph.D.; Dorcas J. Dobie, M.D.; Robert Freedman, M.D.; Michael F. Green, Ph.D.; Ruben C. Gur, Ph.D.; Laura C. Lazzeroni, Ph.D.; Keith H. Nuechterlein, Ph.D.; Ann Olincy, M.D.; Allen D. Radant, M.D.; Amrita Ray, Ph.D.; Nicholas J. Schork, Ph.D.; Larry J. Seidman, Ph.D.; Larry J. Siever, M.D.; Jeremy M. Silverman, Ph.D.; William S. Stone, Ph.D.; Catherine A. Sugar, Ph.D.; Debby W. Tsuang, M.D.; Ming T. Tsuang, M.D., Ph.D., D.Sc.; Bruce I. Turetsky, M.D.; Gregory A. Light, Ph.D.; David L. Braff, M.D.
Am J Psychiatry 2013;170:521-532. doi:10.1176/appi.ajp.2012.12020186
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Dr. Swerdlow has served as a consultant to Neurocrine. Dr. Green has served as a consultant to Abbott Laboratories, Amgen, Biogen, Mnemosyne, Roche, and Shire. Dr. Nuechterlein has received research grant support from Brain Plasticity, Genentech, and Janssen Scientific Affairs and has served as a consultant to Genentech and Otsuka. Dr. Olincy has received research grant support from Lundbeck Pharmaceuticals. Dr. Turetsky has received research grant support from AstraZeneca and Pfizer and consulting fees from Bristol-Myers Squibb and Hoffman-La Roche. Dr. Light has participated in a scientific advisory board meeting for Astellas. All other authors report no financial relationships with commercial interests.

Supported by NIMH grants R01-MH-065588, R01-MH-065562, R01-MH-065707, R01-MH-065554, R01-MH-065578, R01-MH-065558, R01-MH-86135, and K01-MH-087889. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from NIH to Johns Hopkins University (contract number HHSN268200782096C).

From the Department of Psychiatry, University of California San Diego, La Jolla, Calif.; Department of Psychiatry, University of Pennsylvania, Philadelphia; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; VA Puget Sound Health Care System, Seattle; Department of Psychiatry, University of Colorado Denver, Aurora; Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine, University of California Los Angeles; VA Greater Los Angeles Healthcare System, Los Angeles; Departments of Psychiatry and Behavioral Sciences and Pediatrics, Stanford University, Stanford, Calif.; Scripps Translational Science Institute, La Jolla, Calif.; Department of Psychiatry, Harvard Medical School, Boston; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston; Department of Psychiatry, Mount Sinai School of Medicine, New York; James J. Peters VA Medical Center, New York; Department of Biostatistics, University of California Los Angeles School of Public Health; Institute for Genomic Medicine, University of California San Diego, La Jolla; Harvard Institute of Psychiatric Epidemiology and Genetics, Boston; and VISN 22, Mental Illness Research, Education and Clinical Center, VA San Diego Healthcare System, Los Angeles.

Previously presented at the 49th annual meeting of the American College of Neuropsychopharmacology, December 4–8, 2011, Waikoloa, Hawaii.

Address correspondence to Dr. Greenwood (tgreenwood@ucsd.edu) or Dr. Braff (dbraff@ucsd.edu).

Copyright © 2013 by the American Psychiatric Association

Received February 10, 2012; Revised July 05, 2012; Revised September 21, 2012; Accepted October 25, 2012.

Abstract

Objective  The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated.

Method  Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods.

Results  Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23).

Conclusions  Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

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FIGURE 1. Results of the Genome-Wide Single-Nucleotide Polymorphism Linkage Scan in the 296 Families for Each of the Six Primary Neurophysiological and Neurocognitive Endophenotypesa

a Results for the following analyses are shown: the variance components multipoint (red), the pedigree-wide regression multipoint (blue), and the variance components two-point (gray). Log of odds (LOD) scores are indicated on the y-axis, along with the name of the corresponding endophenotype. Chromosomes are aligned along the x-axis end to end with the p-terminus on the left and locations indicated at the top of the graph. Dashed horizontal lines indicate genome-wide significant and suggestive LOD scores of 3.6 and 2.2, respectively. LNS=Letter-Number Span; CVLT-II=California Verbal Learning Test, 2nd edition; DS-CPT=degraded-stimulus Continuous Performance Test; AS=antisaccade task; P50=P50 suppression; PPI=prepulse inhibition.

FIGURE 2. Results of the Genome-Wide Single-Nucleotide Polymorphism Linkage Scan in the 296 Families for Each of the Six Endophenotypes From the University of Pennsylvania Computerized Neurocognitive Batterya

a Results for the following analyses are shown: the variance components multipoint (red), the pedigree-wide regression multipoint (blue), and the variance components two-point (gray). Log of odds (LOD) scores are indicated on the y-axis, along with the name of the corresponding endophenotype. Chromosomes are aligned along the x-axis end to end with the p-terminus on the left and locations indicated at the top of the graph. Dashed horizontal lines indicate genome-wide significant and suggestive LOD scores of 3.6 and 2.2, respectively. EMO=emotion recognition; S-M=sensorimotor dexterity; SPA=spatial processing; SMEM=spatial memory; FMEM=face memory; ABF=abstraction and mental flexibility.

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TABLE 1.Description of 12 Neurophysiological and Neurocognitive Endophenotypes
Table Footer Note

a A modified version of the University of Pennsylvania Computerized Neurocognitive Battery was used to evaluate the “efficiency” of the endophenotype, calculated as accuracy/log10 (speed) and expressed as standard equivalents (Z score).

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TABLE 2.Heritability Estimates Observed for the 12 Endophenotypes in the 296 Families
Table Footer Note

a The 12 endophenotypes are described in Table 1.

Table Footer Note

b Data indicate the number of informative pairs.

Table Footer Note

c Data represent the residual heritability after adjustment for significant covariates.

Table Footer Note

d The proportion of the trait variance explained by all significant covariates.

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TABLE 3.Summary of All Chromosomal Regions With Log of Odds (LOD) Scores Reaching at Least Suggestive Evidence for Linkage
Table Footer Note

a The 12 endophenotypes are described in Table 1.

Table Footer Note

b Data represent analyses conducted using SOLAR 4.3.1 (sequential oligogenic linkage analysis routines).

Table Footer Note

c Genetic and physical boundaries of LOD scores within one unit of the maximum (1-LOD interval); cM=centimorgan, Mb=megabase pairs.

Table Footer Note

d Data represent analyses conducted using MERLIN (multipoint engine for rapid likelihood inference).

Table Footer Note

e Genes within the 1-LOD interval prioritized by proximity to single-nucleotide polymorphisms with two-point LOD scores >1.5.

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References

Karayiorgou  M;  Gogos  JA:  A turning point in schizophrenia genetics.  Neuron 1997; 19:967–979
[CrossRef] | [PubMed]
 
Schork  NJ;  Greenwood  TA;  Braff  DL:  Statistical genetics concepts and approaches in schizophrenia and related neuropsychiatric research.  Schizophr Bull 2007; 33:95–104
[CrossRef] | [PubMed]
 
Sullivan  PF:  The genetics of schizophrenia.  PLoS Med 2005; 2:e212
[CrossRef] | [PubMed]
 
Harrison  PJ;  Weinberger  DR:  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.  Mol Psychiatry 2005; 10:40–68; image 45; Erratum in  Mol Psychiatry 2005; 10:804 and 10:420
[CrossRef] | [PubMed]
 
Gogos  JA;  Gerber  DJ:  Schizophrenia susceptibility genes: emergence of positional candidates and future directions.  Trends Pharmacol Sci 2006; 27:226–233
[CrossRef] | [PubMed]
 
Baron  M:  Genetics of schizophrenia and the new millennium: progress and pitfalls.  Am J Hum Genet 2001; 68:299–312
[CrossRef] | [PubMed]
 
Bleuler  E:  Dementia Praecox oder Gruppe der Schizophrenien .  Leipzig,  Deuticke, 1911
 
Braff  DL;  Freedman  R:  The importance of endophenotypes in studies of the genetics of schizophrenia, in  Neuropsychopharmacology: The Fifth Generation of Progress . Edited by Davis  KL;  Charney  D;  Coyle  JT;  Nemeroff  C.  Baltimore,  Lippincott, Williams & Wilkins, 2002, pp 703–716
 
Braff  D;  Schork  NJ;  Gottesman  II:  Endophenotyping schizophrenia.  Am J Psychiatry 2007; 164:705–707
[CrossRef] | [PubMed]
 
Gottesman  II;  Gould  TD:  The endophenotype concept in psychiatry: etymology and strategic intentions.  Am J Psychiatry 2003; 160:636–645
[CrossRef] | [PubMed]
 
Altshuler  D;  Daly  MJ;  Lander  ES:  Genetic mapping in human disease.  Science 2008; 322:881–888
[CrossRef] | [PubMed]
 
Manolio  TA;  Collins  FS;  Cox  NJ;  Goldstein  DB;  Hindorff  LA;  Hunter  DJ;  McCarthy  MI;  Ramos  EM;  Cardon  LR;  Chakravarti  A;  Cho  JH;  Guttmacher  AE;  Kong  A;  Kruglyak  L;  Mardis  E;  Rotimi  CN;  Slatkin  M;  Valle  D;  Whittemore  AS;  Boehnke  M;  Clark  AG;  Eichler  EE;  Gibson  G;  Haines  JL;  Mackay  TF;  McCarroll  SA;  Visscher  PM:  Finding the missing heritability of complex diseases.  Nature 2009; 461:747–753
[CrossRef] | [PubMed]
 
Roeder  K;  Bacanu  SA;  Wasserman  L;  Devlin  B:  Using linkage genome scans to improve power of association in genome scans.  Am J Hum Genet 2006; 78:243–252
[CrossRef] | [PubMed]
 
Braff  D;  Stone  C;  Callaway  E;  Geyer  M;  Glick  I;  Bali  L:  Prestimulus effects on human startle reflex in normals and schizophrenics.  Psychophysiology 1978; 15:339–343
[CrossRef] | [PubMed]
 
Braff  DL;  Geyer  MA;  Swerdlow  NR:  Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.  Psychopharmacology (Berl) 2001; 156:234–258
[CrossRef] | [PubMed]
 
Swerdlow  NR;  Sprock  J;  Light  GA;  Cadenhead  K;  Calkins  ME;  Dobie  DJ;  Freedman  R;  Green  MF;  Greenwood  TA;  Gur  RE;  Mintz  J;  Olincy  A;  Nuechterlein  KH;  Radant  AD;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Tsuang  DW;  Tsuang  MT;  Turetsky  BI;  Braff  DL:  Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia.  Schizophr Res 2007; 92:237–251
[CrossRef] | [PubMed]
 
Anokhin  AP;  Vedeniapin  AB;  Heath  AC;  Korzyukov  O;  Boutros  NN:  Genetic and environmental influences on sensory gating of mid-latency auditory evoked responses: a twin study.  Schizophr Res 2007; 89:312–319
[CrossRef] | [PubMed]
 
Freedman  R;  Coon  H;  Myles-Worsley  M;  Orr-Urtreger  A;  Olincy  A;  Davis  A;  Polymeropoulos  M;  Holik  J;  Hopkins  J;  Hoff  M;  Rosenthal  J;  Waldo  MC;  Reimherr  F;  Wender  P;  Yaw  J;  Young  DA;  Breese  CR;  Adams  C;  Patterson  D;  Adler  LE;  Kruglyak  L;  Leonard  S;  Byerley  W:  Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.  Proc Natl Acad Sci USA 1997; 94:587–592
[CrossRef] | [PubMed]
 
Olincy  A;  Braff  DL;  Adler  LE;  Cadenhead  KS;  Calkins  ME;  Dobie  DJ;  Green  MF;  Greenwood  TA;  Gur  RE;  Gur  RC;  Light  GA;  Mintz  J;  Nuechterlein  KH;  Radant  AD;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  DW;  Tsuang  MT;  Turetsky  BI;  Wagner  BD;  Freedman  R:  Inhibition of the P50 cerebral evoked response to repeated auditory stimuli: results from the Consortium on Genetics of Schizophrenia.  Schizophr Res 2010; 119:175–182
[CrossRef] | [PubMed]
 
Radant  AD;  Dobie  DJ;  Calkins  ME;  Olincy  A;  Braff  DL;  Cadenhead  KS;  Freedman  R;  Green  MF;  Greenwood  TA;  Gur  RE;  Gur  RC;  Light  GA;  Meichle  SP;  Millard  SP;  Mintz  J;  Nuechterlein  KH;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  MT;  Turetsky  BI;  Tsuang  DW:  Antisaccade performance in schizophrenia patients, their first-degree biological relatives, and community comparison subjects: data from the COGS study.  Psychophysiology 2010; 47:846–856
[PubMed]
 
Radant  AD;  Dobie  DJ;  Calkins  ME;  Olincy  A;  Braff  DL;  Cadenhead  KS;  Freedman  R;  Green  MF;  Greenwood  TA;  Gur  RE;  Light  GA;  Meichle  SP;  Mintz  J;  Nuechterlein  KH;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  MT;  Turetsky  BI;  Tsuang  DW:  Successful multi-site measurement of antisaccade performance deficits in schizophrenia.  Schizophr Res 2007; 89:320–329
[CrossRef] | [PubMed]
 
Nuechterlein  KH;  Asarnow  RF:  Degraded Stimulus Continuous Performance Test (DS-CPT) Program for IBM-Compatible Microcomputers, Version 8.12 .  Los Angeles,  Nuechterlein and Asarnow, 1999
 
Nuechterlein  KH;  Parasuraman  R;  Jiang  Q:  Visual sustained attention: image degradation produces rapid sensitivity decrement over time.  Science 1983; 220:327–329
[CrossRef] | [PubMed]
 
Delis  DC;  Kramer  JH;  Kaplan  E;  Ober  BA:  California Verbal Learning Test, 2nd ed, Adult Version .  San Antonio, Tex,  Psychological Corporation, 2000
 
Stone  WS;  Giuliano  AJ;  Tsuang  MT;  Braff  DL;  Cadenhead  KS;  Calkins  ME;  Dobie  DJ;  Faraone  SV;  Freedman  R;  Green  MF;  Greenwood  TA;  Gur  RE;  Gur  RC;  Light  GA;  Mintz  J;  Nuechterlein  KH;  Olincy  A;  Radant  AD;  Roe  AH;  Schork  NJ;  Siever  LJ;  Silverman  JM;  Swerdlow  NR;  Thomas  AR;  Tsuang  DW;  Turetsky  BI;  Seidman  LJ:  Group and site differences on the California Verbal Learning Test in persons with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia (COGS).  Schizophr Res 2011; 128:102–110
[CrossRef] | [PubMed]
 
Gold  JM;  Carpenter  C;  Randolph  C;  Goldberg  TE;  Weinberger  DR:  Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia.  Arch Gen Psychiatry 1997; 54:159–165
[CrossRef] | [PubMed]
 
Horan  WP;  Braff  DL;  Nuechterlein  KH;  Sugar  CA;  Cadenhead  KS;  Calkins  ME;  Dobie  DJ;  Freedman  R;  Greenwood  TA;  Gur  RE;  Gur  RC;  Light  GA;  Mintz  J;  Olincy  A;  Radant  AD;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  DW;  Tsuang  MT;  Turetsky  BI;  Green  MF:  Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia.  Schizophr Res 2008; 103:218–228
[CrossRef] | [PubMed]
 
Perry  W;  Heaton  RK;  Potterat  E;  Roebuck  T;  Minassian  A;  Braff  DL:  Working memory in schizophrenia: transient “online” storage versus executive functioning.  Schizophr Bull 2001; 27:157–176
[CrossRef] | [PubMed]
 
Gur  RC;  Ragland  JD;  Moberg  PJ;  Turner  TH;  Bilker  WB;  Kohler  C;  Siegel  SJ;  Gur  RE:  Computerized neurocognitive scanning: I. Methodology and validation in healthy people.  Neuropsychopharmacology 2001; 25:766–776
[CrossRef] | [PubMed]
 
Gur  RC;  Ragland  JD;  Moberg  PJ;  Bilker  WB;  Kohler  C;  Siegel  SJ;  Gur  RE:  Computerized neurocognitive scanning: II. The profile of schizophrenia.  Neuropsychopharmacology 2001; 25:777–788
[CrossRef] | [PubMed]
 
Calkins  ME;  Dobie  DJ;  Cadenhead  KS;  Olincy  A;  Freedman  R;  Green  MF;  Greenwood  TA;  Gur  RE;  Gur  RC;  Light  GA;  Mintz  J;  Nuechterlein  KH;  Radant  AD;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  DW;  Tsuang  MT;  Turetsky  BI;  Braff  DL:  The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.  Schizophr Bull 2007; 33:33–48
[CrossRef] | [PubMed]
 
Gur  RE;  Calkins  ME;  Gur  RC;  Horan  WP;  Nuechterlein  KH;  Seidman  LJ;  Stone  WS:  The consortium on the genetics of schizophrenia: neurocognitive endophenotypes.  Schizophr Bull 2007; 33:49–68
[CrossRef] | [PubMed]
 
Turetsky  BI;  Calkins  ME;  Light  GA;  Olincy  A;  Radant  AD;  Swerdlow  NR:  Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures.  Schizophr Bull 2007; 33:69–94
[CrossRef] | [PubMed]
 
Greenwood  TA;  Braff  DL;  Light  GA;  Cadenhead  KS;  Calkins  ME;  Dobie  DJ;  Freedman  R;  Green  MF;  Gur  RE;  Gur  RC;  Mintz  J;  Nuechterlein  KH;  Olincy  A;  Radant  AD;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  DW;  Tsuang  MT;  Turetsky  BI;  Schork  NJ:  Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia.  Arch Gen Psychiatry 2007; 64:1242–1250
[CrossRef] | [PubMed]
 
Greenwood  TA;  Lazzeroni  LC;  Murray  SS;  Cadenhead  KS;  Calkins  ME;  Dobie  DJ;  Green  MF;  Gur  RE;  Gur  RC;  Hardiman  G;  Kelsoe  JR;  Leonard  S;  Light  GA;  Nuechterlein  KH;  Olincy  A;  Radant  AD;  Schork  NJ;  Seidman  LJ;  Siever  LJ;  Silverman  JM;  Stone  WS;  Swerdlow  NR;  Tsuang  DW;  Tsuang  MT;  Turetsky  BI;  Freedman  R;  Braff  DL:  Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia.  Am J Psychiatry 2011; 168:930–946
[CrossRef] | [PubMed]
 
American Psychiatric Association:  Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision .  Washington, DC,  American Psychiatric Publishing, 2000
 
Faraone  SV;  Tsuang  D;  Tsuang  MT:  Genetics of Mental Disorders: A Guide for Students, Clinicians, and Researchers .  New York,  Guilford, 1999
 
Nurnberger  JI  Jr;  Blehar  MC;  Kaufmann  CA;  York-Cooler  C;  Simpson  SG;  Harkavy-Friedman  J;  Severe  JB;  Malaspina  D;  Reich  T:  Diagnostic interview for genetic studies: rationale, unique features, and training: NIMH Genetics Initiative.  Arch Gen Psychiatry 1994; 51:849–859
[CrossRef] | [PubMed]
 
O’Connell  JR;  Weeks  DE:  PedCheck: a program for identification of genotype incompatibilities in linkage analysis.  Am J Hum Genet 1998; 63:259–266
[CrossRef] | [PubMed]
 
Abecasis  GR;  Cherny  SS;  Cookson  WO;  Cardon  LR:  Merlin: rapid analysis of dense genetic maps using sparse gene flow trees.  Nat Genet 2002; 30:97–101
[CrossRef] | [PubMed]
 
Kong  A;  Gudbjartsson  DF;  Sainz  J;  Jonsdottir  GM;  Gudjonsson  SA;  Richardsson  B;  Sigurdardottir  S;  Barnard  J;  Hallbeck  B;  Masson  G;  Shlien  A;  Palsson  ST;  Frigge  ML;  Thorgeirsson  TE;  Gulcher  JR;  Stefansson  K:  A high-resolution recombination map of the human genome.  Nat Genet 2002; 31:241–247
[PubMed]
 
Almasy  L;  Blangero  J:  Multipoint quantitative-trait linkage analysis in general pedigrees.  Am J Hum Genet 1998; 62:1198–1211
[CrossRef] | [PubMed]
 
Almasy  L;  Dyer  TD;  Blangero  J:  Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages.  Genet Epidemiol 1997; 14:953–958
[CrossRef] | [PubMed]
 
Wigginton  JE;  Abecasis  GR:  PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data.  Bioinformatics 2005; 21:3445–3447
[CrossRef] | [PubMed]
 
Beaty  TH;  Liang  KY:  Robust inference for variance components models in families ascertained through probands: I. Conditioning on proband’s phenotype.  Genet Epidemiol 1987; 4:203–210
[CrossRef] | [PubMed]
 
Blangero  J;  Williams  JT;  Almasy  L:  Robust LOD scores for variance component-based linkage analysis.  Genet Epidemiol 2000; 19(Suppl 1):S8–S14
[CrossRef] | [PubMed]
 
Sham  PC;  Purcell  S;  Cherny  SS;  Abecasis  GR:  Powerful regression-based quantitative-trait linkage analysis of general pedigrees.  Am J Hum Genet 2002; 71:238–253
[CrossRef] | [PubMed]
 
Schork  NJ;  Greenwood  TA:  Inherent bias toward the null hypothesis in conventional multipoint nonparametric linkage analysis.  Am J Hum Genet 2004; 74:306–316
[CrossRef] | [PubMed]
 
Schork  NJ;  Greenwood  TA:  Got bias? The authors reply.  Am J Hum Genet 2004; 75:723–727
[CrossRef]
 
Lander  E;  Kruglyak  L:  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.  Nat Genet 1995; 11:241–247
[CrossRef] | [PubMed]
 
Benton  CS;  de Silva  R;  Rutledge  SL;  Bohlega  S;  Ashizawa  T;  Zoghbi  HY:  Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype.  Neurology 1998; 51:1081–1086
[CrossRef] | [PubMed]
 
Fallin  MD;  Lasseter  VK;  Avramopoulos  D;  Nicodemus  KK;  Wolyniec  PS;  McGrath  JA;  Steel  G;  Nestadt  G;  Liang  KY;  Huganir  RL;  Valle  D;  Pulver  AE:  Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.  Am J Hum Genet 2005; 77:918–936
[CrossRef] | [PubMed]
 
Joo  EJ;  Lee  JH;  Cannon  TD;  Price  RA:  Possible association between schizophrenia and a CAG repeat polymorphism in the spinocerebellar ataxia type 1 (SCA1) gene on human chromosome 6p23.  Psychiatr Genet 1999; 9:7–11
[CrossRef] | [PubMed]
 
Kohen  R;  Metcalf  MA;  Khan  N;  Druck  T;  Huebner  K;  Lachowicz  JE;  Meltzer  HY;  Sibley  DR;  Roth  BL;  Hamblin  MW:  Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.  J Neurochem 1996; 66:47–56
[CrossRef] | [PubMed]
 
O’Donovan  MC;  Craddock  N;  Norton  N;  Williams  H;  Peirce  T;  Moskvina  V;  Nikolov  I;  Hamshere  M;  Carroll  L;  Georgieva  L;  Dwyer  S;  Holmans  P;  Marchini  JL;  Spencer  CC;  Howie  B;  Leung  HT;  Hartmann  AM;  Möller  HJ;  Morris  DW;  Shi  Y;  Feng  G;  Hoffmann  P;  Propping  P;  Vasilescu  C;  Maier  W;  Rietschel  M;  Zammit  S;  Schumacher  J;  Quinn  EM;  Schulze  TG;  Williams  NM;  Giegling  I;  Iwata  N;  Ikeda  M;  Darvasi  A;  Shifman  S;  He  L;  Duan  J;  Sanders  AR;  Levinson  DF;  Gejman  PV;  Cichon  S;  Nöthen  MM;  Gill  M;  Corvin  A;  Rujescu  D;  Kirov  G;  Owen  MJ;  Buccola  NG;  Mowry  BJ;  Freedman  R;  Amin  F;  Black  DW;  Silverman  JM;  Byerley  WF;  Cloninger  CR; Molecular Genetics of Schizophrenia Collaboration:  Identification of loci associated with schizophrenia by genome-wide association and follow-up.  Nat Genet 2008; 40:1053–1055
[CrossRef] | [PubMed]
 
Purcell  SM;  Wray  NR;  Stone  JL;  Visscher  PM;  O’Donovan  MC;  Sullivan  PF;  Sklar  P; International Schizophrenia Consortium:  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.  Nature 2009; 460:748–752
[PubMed]
 
Williams  HJ;  Norton  N;  Dwyer  S;  Moskvina  V;  Nikolov  I;  Carroll  L;  Georgieva  L;  Williams  NM;  Morris  DW;  Quinn  EM;  Giegling  I;  Ikeda  M;  Wood  J;  Lencz  T;  Hultman  C;  Lichtenstein  P;  Thiselton  D;  Maher  BS;  Malhotra  AK;  Riley  B;  Kendler  KS;  Gill  M;  Sullivan  P;  Sklar  P;  Purcell  S;  Nimgaonkar  VL;  Kirov  G;  Holmans  P;  Corvin  A;  Rujescu  D;  Craddock  N;  Owen  MJ;  O’Donovan  MC; Molecular Genetics of Schizophrenia Collaboration (MGS) International Schizophrenia Consortium (ISC), SGENE-plus, GROUP:  Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder.  Mol Psychiatry 2011; 16:429–441
[CrossRef] | [PubMed]
 
Greenwood  TA;  Light  GA;  Swerdlow  NR;  Radant  AD;  Braff  DL:  Association analysis of 94 candidate genes and schizophrenia-related endophenotypes.  PLoS ONE 2011; 168:930–946
 
Stöber  G;  Sprandel  J;  Jabs  B;  Pfuhlmann  B;  Möller-Ehrlich  K;  Knapp  M:  Family-based study of markers at the 5′-flanking region of the human dopamine transporter gene reveals potential association with schizophrenic psychoses.  Eur Arch Psychiatry Clin Neurosci 2006; 256:422–427
[CrossRef] | [PubMed]
 
Ralph  RJ;  Paulus  MP;  Fumagalli  F;  Caron  MG;  Geyer  MA:  Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists.  J Neurosci 2001; 21:305–313
[PubMed]
 
Di Maria  E;  Gulli  R;  Begni  S;  De Luca  A;  Bignotti  S;  Pasini  A;  Bellone  E;  Pizzuti  A;  Dallapiccola  B;  Novelli  G;  Ajmar  F;  Gennarelli  M;  Mandich  P:  Variations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study.  Am J Med Genet B Neuropsychiatr Genet 2004; 128B:27–29
[CrossRef] | [PubMed]
 
Li  D;  He  L:  Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: a HuGE review and meta-analysis.  Genet Med 2007; 9:4–8
[CrossRef] | [PubMed]
 
Ohtsuki  T;  Sakurai  K;  Dou  H;  Toru  M;  Yamakawa-Kobayashi  K;  Arinami  T:  Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.  Mol Psychiatry 2001; 6:211–216
[CrossRef] | [PubMed]
 
Ikeda  M;  Hikita  T;  Taya  S;  Uraguchi-Asaki  J;  Toyo-oka  K;  Wynshaw-Boris  A;  Ujike  H;  Inada  T;  Takao  K;  Miyakawa  T;  Ozaki  N;  Kaibuchi  K;  Iwata  N:  Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.  Hum Mol Genet 2008; 17:3212–3222
[CrossRef] | [PubMed]
 
Moens  LN;  De Rijk  P;  Reumers  J;  Van den Bossche  MJ;  Glassee  W;  De Zutter  S;  Lenaerts  AS;  Nordin  A;  Nilsson  LG;  Medina Castello  I;  Norrback  KF;  Goossens  D;  Van Steen  K;  Adolfsson  R;  Del-Favero  J:  Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population.  PLoS ONE 2011; 6:e23450
[CrossRef] | [PubMed]
 
Holmans  PA;  Riley  B;  Pulver  AE;  Owen  MJ;  Wildenauer  DB;  Gejman  PV;  Mowry  BJ;  Laurent  C;  Kendler  KS;  Nestadt  G;  Williams  NM;  Schwab  SG;  Sanders  AR;  Nertney  D;  Mallet  J;  Wormley  B;  Lasseter  VK;  O’Donovan  MC;  Duan  J;  Albus  M;  Alexander  M;  Godard  S;  Ribble  R;  Liang  KY;  Norton  N;  Maier  W;  Papadimitriou  G;  Walsh  D;  Jay  M;  O’Neill  A;  Lerer  FB;  Dikeos  D;  Crowe  RR;  Silverman  JM;  Levinson  DF:  Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms.  Mol Psychiatry 2009; 14:786–795
[CrossRef] | [PubMed]
 
Hamshere  ML;  Holmans  PA;  McCarthy  GM;  Jones  LA;  Murphy  KC;  Sanders  RD;  Gray  MY;  Zammit  S;  Williams  NM;  Norton  N;  Williams  HJ;  McGuffin  P;  O’Donovan  MC;  Craddock  N;  Owen  MJ;  Cardno  AG:  Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia.  Am J Med Genet B Neuropsychiatr Genet 2011; 156B:929–940
[PubMed]
 
Lien  YJ;  Liu  CM;  Faraone  SV;  Tsuang  MT;  Hwu  HG;  Hsiao  PC;  Chen  WJ:  A genome-wide quantitative trait loci scan of neurocognitive performances in families with schizophrenia.  Genes Brain Behav 2010; 9:695–702
[CrossRef] | [PubMed]
 
Almasy  L;  Gur  RC;  Haack  K;  Cole  SA;  Calkins  ME;  Peralta  JM;  Hare  E;  Prasad  K;  Pogue-Geile  MF;  Nimgaonkar  V;  Gur  RE:  A genome screen for quantitative trait loci influencing schizophrenia and neurocognitive phenotypes.  Am J Psychiatry 2008; 165:1185–1192
[CrossRef] | [PubMed]
 
Cao  Q;  Martinez  M;  Zhang  J;  Sanders  AR;  Badner  JA;  Cravchik  A;  Markey  CJ;  Beshah  E;  Guroff  JJ;  Maxwell  ME;  Kazuba  DM;  Whiten  R;  Goldin  LR;  Gershon  ES;  Gejman  PV:  Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees.  Genomics 1997; 43:1–8
[CrossRef] | [PubMed]
 
Coon  H;  Holik  J;  Hoff  M;  Reimherr  F;  Wender  P;  Myles-Worsley  M;  Waldo  M;  Freedman  R;  Byerley  W:  Analysis of chromosome 22 markers in nine schizophrenia pedigrees.  Am J Med Genet 1994; 54:72–79
[CrossRef] | [PubMed]
 
Lasseter  VK;  Pulver  AE;  Wolyniec  PS;  Nestadt  G;  Meyers  D;  Karayiorgou  M;  Housman  D;  Antonarakis  S;  Kazazian  H;  Kasch  L  et al:  Follow-up report of potential linkage for schizophrenia on chromosome 22q, part 3.  Am J Med Genet 1995; 60:172–173
[CrossRef] | [PubMed]
 
Leonard  S;  Gault  J;  Moore  T;  Hopkins  J;  Robinson  M;  Olincy  A;  Adler  LE;  Cloninger  CR;  Kaufmann  CA;  Tsuang  MT;  Faraone  SV;  Malaspina  D;  Svrakic  DM;  Freedman  R:  Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative.  Am J Med Genet 1998; 81:308–312
[CrossRef] | [PubMed]
 
Martinez  M;  Goldin  LR;  Cao  Q;  Zhang  J;  Sanders  AR;  Nancarrow  DJ;  Taylor  JM;  Levinson  DF;  Kirby  A;  Crowe  RR;  Andreasen  NC;  Black  DW;  Silverman  JM;  Lennon  DP;  Nertney  DA;  Brown  DM;  Mowry  BJ;  Gershon  ES;  Gejman  PV:  Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.  Am J Med Genet 1999; 88:337–343
[CrossRef] | [PubMed]
 
Polymeropoulos  MH;  Coon  H;  Byerley  W;  Gershon  ES;  Goldin  L;  Crow  TJ;  Rubenstein  J;  Hoff  M;  Holik  J;  Smith  AM  et al:  Search for a schizophrenia susceptibility locus on human chromosome 22.  Am J Med Genet 1994; 54:93–99
[CrossRef] | [PubMed]
 
Pulver  AE;  Karayiorgou  M;  Wolyniec  PS;  Lasseter  VK;  Kasch  L;  Nestadt  G;  Antonarakis  S;  Housman  D;  Kazazian  HH;  Meyers  D  et al:  Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1.  Am J Med Genet 1994; 54:36–43
[CrossRef] | [PubMed]
 
Stöber  G;  Saar  K;  Rüschendorf  F;  Meyer  J;  Nürnberg  G;  Jatzke  S;  Franzek  E;  Reis  A;  Lesch  KP;  Wienker  TF;  Beckmann  H:  Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15.  Am J Hum Genet 2000; 67:1201–1207
[PubMed]
 
Prasad  SE;  Howley  S;  Murphy  KC:  Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome.  Dev Disabil Res Rev 2008; 14:26–34
[CrossRef] | [PubMed]
 
Badner  JA;  Gershon  ES:  Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.  Mol Psychiatry 2002; 7:405–411
[CrossRef] | [PubMed]
 
Myles-Worsley  M;  Coon  H;  McDowell  J;  Brenner  C;  Hoff  M;  Lind  B;  Bennett  P;  Freedman  R;  Clementz  B;  Byerley  W:  Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families.  Am J Med Genet 1999; 88:544–550
[CrossRef] | [PubMed]
 
International Schizophrenia Consortium:  Rare chromosomal deletions and duplications increase risk of schizophrenia.  Nature 2008; 455:237–241
[CrossRef] | [PubMed]
 
Guilmatre  A;  Dubourg  C;  Mosca  AL;  Legallic  S;  Goldenberg  A;  Drouin-Garraud  V;  Layet  V;  Rosier  A;  Briault  S;  Bonnet-Brilhault  F;  Laumonnier  F;  Odent  S;  Le Vacon  G;  Joly-Helas  G;  David  V;  Bendavid  C;  Pinoit  JM;  Henry  C;  Impallomeni  C;  Germano  E;  Tortorella  G;  Di Rosa  G;  Barthelemy  C;  Andres  C;  Faivre  L;  Frébourg  T;  Saugier Veber  P;  Campion  D:  Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.  Arch Gen Psychiatry 2009; 66:947–956
[CrossRef] | [PubMed]
 
Kirov  G;  Grozeva  D;  Norton  N;  Ivanov  D;  Mantripragada  KK;  Holmans  P;  Craddock  N;  Owen  MJ;  O’Donovan  MC; International Schizophrenia Consortium Wellcome Trust Case Control Consortium:  Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.  Hum Mol Genet 2009; 18:1497–1503
[CrossRef] | [PubMed]
 
Stefansson  H;  Rujescu  D;  Cichon  S;  Pietiläinen  OP;  Ingason  A;  Steinberg  S;  Fossdal  R;  Sigurdsson  E;  Sigmundsson  T;  Buizer-Voskamp  JE;  Hansen  T;  Jakobsen  KD;  Muglia  P;  Francks  C;  Matthews  PM;  Gylfason  A;  Halldorsson  BV;  Gudbjartsson  D;  Thorgeirsson  TE;  Sigurdsson  A;  Jonasdottir  A;  Jonasdottir  A;  Bjornsson  A;  Mattiasdottir  S;  Blondal  T;  Haraldsson  M;  Magnusdottir  BB;  Giegling  I;  Möller  HJ;  Hartmann  A;  Shianna  KV;  Ge  D;  Need  AC;  Crombie  C;  Fraser  G;  Walker  N;  Lonnqvist  J;  Suvisaari  J;  Tuulio-Henriksson  A;  Paunio  T;  Toulopoulou  T;  Bramon  E;  Di Forti  M;  Murray  R;  Ruggeri  M;  Vassos  E;  Tosato  S;  Walshe  M;  Li  T;  Vasilescu  C;  Mühleisen  TW;  Wang  AG;  Ullum  H;  Djurovic  S;  Melle  I;  Olesen  J;  Kiemeney  LA;  Franke  B;  Sabatti  C;  Freimer  NB;  Gulcher  JR;  Thorsteinsdottir  U;  Kong  A;  Andreassen  OA;  Ophoff  RA;  Georgi  A;  Rietschel  M;  Werge  T;  Petursson  H;  Goldstein  DB;  Nöthen  MM;  Peltonen  L;  Collier  DA;  St Clair  D;  Stefansson  K; GROUP:  Large recurrent microdeletions associated with schizophrenia.  Nature 2008; 455:232–236
[CrossRef] | [PubMed]
 
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium:  Genome-wide association study identifies five new schizophrenia loci.  Nat Genet 2011; 43:969–976
[CrossRef] | [PubMed]
 
Stefansson  H;  Ophoff  RA;  Steinberg  S;  Andreassen  OA;  Cichon  S;  Rujescu  D;  Werge  T;  Pietiläinen  OP;  Mors  O;  Mortensen  PB;  Sigurdsson  E;  Gustafsson  O;  Nyegaard  M;  Tuulio-Henriksson  A;  Ingason  A;  Hansen  T;  Suvisaari  J;  Lonnqvist  J;  Paunio  T;  Børglum  AD;  Hartmann  A;  Fink-Jensen  A;  Nordentoft  M;  Hougaard  D;  Norgaard-Pedersen  B;  Böttcher  Y;  Olesen  J;  Breuer  R;  Möller  HJ;  Giegling  I;  Rasmussen  HB;  Timm  S;  Mattheisen  M;  Bitter  I;  Réthelyi  JM;  Magnusdottir  BB;  Sigmundsson  T;  Olason  P;  Masson  G;  Gulcher  JR;  Haraldsson  M;  Fossdal  R;  Thorgeirsson  TE;  Thorsteinsdottir  U;  Ruggeri  M;  Tosato  S;  Franke  B;  Strengman  E;  Kiemeney  LA;  Melle  I;  Djurovic  S;  Abramova  L;  Kaleda  V;  Sanjuan  J;  de Frutos  R;  Bramon  E;  Vassos  E;  Fraser  G;  Ettinger  U;  Picchioni  M;  Walker  N;  Toulopoulou  T;  Need  AC;  Ge  D;  Yoon  JL;  Shianna  KV;  Freimer  NB;  Cantor  RM;  Murray  R;  Kong  A;  Golimbet  V;  Carracedo  A;  Arango  C;  Costas  J;  Jönsson  EG;  Terenius  L;  Agartz  I;  Petursson  H;  Nöthen  MM;  Rietschel  M;  Matthews  PM;  Muglia  P;  Peltonen  L;  St Clair  D;  Goldstein  DB;  Stefansson  K;  Collier  DA; Genetic Risk and Outcome in Psychosis (GROUP):  Common variants conferring risk of schizophrenia.  Nature 2009; 460:744–747
[PubMed]
 
So  HC;  Gui  AH;  Cherny  SS;  Sham  PC:  Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases.  Genet Epidemiol 2011; 35:310–317
[CrossRef] | [PubMed]
 
Flint  J;  Munafò  MR:  The endophenotype concept in psychiatric genetics.  Psychol Med 2007; 37:163–180
[CrossRef] | [PubMed]
 
Swerdlow  NR:  Integrative circuit models and their implications for the pathophysiologies and treatments of the schizophrenias. The Behavioral Neurobiology of Schizophrenia and its Treatment, in  Current Topics in Behavioral Neuroscience . Edited by Geyer  MA;  Ellenbroek  BA;  Marsden  CA.  New York,  Springer, 2010, pp 555–586
 
Swerdlow  NR;  Geyer  MA;  Braff  DL:  Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges.  Psychopharmacology (Berl) 2001; 156:194–215
[CrossRef] | [PubMed]
 
Braff  DL:  Promises and Challenges of Translational Research in Neuropsychiatry, in  Translational Neuroscience: Applications in Neurology, Psychiatry, and Neurodevelopmental Disorders . Edited by Barrett  JE;  Coyle  JT;  Williams  M.  New York,  Cambridge University Press, 2012, pp 339–358
 
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