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Prenatal Expression Patterns of Genes Associated With Neuropsychiatric Disorders
Rebecca Birnbaum, M.D.; Andrew E. Jaffe, Ph.D.; Thomas M. Hyde, M.D., Ph.D.; Joel E. Kleinman, M.D., Ph.D.; Daniel R. Weinberger, M.D.
Am J Psychiatry 2014;171:758-767. doi:10.1176/appi.ajp.2014.13111452
View Author and Article Information

Dr. Birnbaum receives support from an NIH T32, 5T32MH015330-36

The authors report no financial relationships with commercial interests.

From the Lieber Institute for Brain Development, Baltimore, and the Departments of Psychiatry, Neurology, Neuroscience, and The Institute of Genetic Medicine, Johns Hopkins School of Medicine, Balitmore.

Address correspondence to Dr. Weinberger (drweinberger@libd.org).

Copyright © 2014 by the American Psychiatric Association

Received November 03, 2013; Revised January 28, 2014; Accepted February 21, 2014.

Abstract

Objective  Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed).

Method  The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based “BrainCloud” dorsolateral prefrontal cortex transcriptome.

Results  Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10–3), intellectual disability (N=88 genes, p=5.53×10–3), and autism spectrum disorder (N=242 genes, p=3.45×10–4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10–3).

Conclusions  The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

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FIGURE 1. Fetal Effect by Individual Gene Calculated for Each Gene Expressing a Transcript in the Dorsolateral Prefrontal Cortexa

a Two examples are illustrated. The fetal effect is prenatal compared with postnatal log2-fold change or regression coefficient. N=269 control samples (including 38 fetal samples). The x axis represents time course, with fetal stage in weeks and postnatal stage in years. Plots above are obtained from BrainCloud application (http://braincloud.jhmi.edu/).

FIGURE 2. Density Plot of Fetal Effect by Gene Set and Wilcoxon Signed-Rank Testa

a The figures depict the density of each gene set’s fetal effect compared to the fetal effect of the whole genome. The x axis is the fetal effect, or regression coefficient (prenatal compared with postnatal) and the y axis is the density. The black line indicates the genome and each colored line indicates the gene set. The red line indicates significant increase, the purple line indicates significant decrease, and the blue line (default) indicates no significant difference in fetal effect of gene set compared to the transcriptome. One-sided p values are shown for Wilcoxon signed-rank test for each gene set, elevation in the positive direction on the upper right side, and decrease in the negative direction on the upper left side.

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TABLE 1.Fetal Effect by Gene Set and Binomial Testa
Table Footer Note

a The percentage of genes within each gene set that are preferentially fetally expressed by increasing stringency of fetal effect: 0.5, 1.0, and 1.5. Two-sided p values for binomial proportion tests are listed. Shading indicates significant elevation compared to the genome and bolding indicates significant decrease compared to the genome [see article PDF for shading]. ASD=autism spectrum disorder; CNV=copy number variant; SNV=single nucleotide variant; INDEL=short insertion/deletion; GWAS=genome-wide association study; SRF=Schizophrenia Research Forum; PGC=Psychiatric Genomics Consortium.

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TABLE 2.Genes Within Copy Number Variant (CNV) Regions Associated With Schizophrenia and Autism Spectrum Disorder (ASD)a
Table Footer Note

a Genes with a fetal effect greater than 0.5 are in bold and genes with a fetal effect greater than 1 are shaded [see article PDF for shading]; Genes with no microarray probes are indicated as n/a.

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TABLE 3.Other Schizophrenia-Associated CNV Locia
Table Footer Note

a Genes with a fetal effect greater than 0.5 are in bold and genes with a fetal effect greater than 1 are shaded [see article PDF for shading]; Genes with no microarray probes are indicated as n/a. CNV=copy number variant.

Anchor for Jump
TABLE 4.Other Autism Spectrum Disorder-Associated CNV Locia
Table Footer Note

a Genes with a fetal effect greater than 0.5 are in bold and genes with a fetal effect greater than 1 are shaded [see article PDF for shading]; Genes with no microarray probes are indicated as n/a. CNV=copy number variant.

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References

Weinberger  DR:  Implications of normal brain development for the pathogenesis of schizophrenia.  Arch Gen Psychiatry 1987; 44:660–669
[CrossRef] | [PubMed]
 
Murray  RM;  Lewis  SW:  Is schizophrenia a neurodevelopmental disorder? Br Med J (Clin Res Ed) 1987; 295:681–682
[CrossRef] | [PubMed]
 
Feinberg  I:  Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1982-1983-1983; 17:319–334
[CrossRef]
 
Susser  E;  Neugebauer  R;  Hoek  HW;  Brown  AS;  Lin  S;  Labovitz  D;  Gorman  JM:  Schizophrenia after prenatal famine: further evidence.  Arch Gen Psychiatry 1996; 53:25–31
[CrossRef] | [PubMed]
 
Brown  AS:  Exposure to prenatal infection and risk of schizophrenia.  Front Psychiatry 2011; 2:63
[CrossRef] | [PubMed]
 
Weinberg  SM;  Jenkins  EA;  Marazita  ML;  Maher  BS:  Minor physical anomalies in schizophrenia: a meta-analysis.  Schizophr Res 2007; 89:72–85
[CrossRef] | [PubMed]
 
Lewis  SW;  Murray  RM:  Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia.  J Psychiatr Res 1987; 21:413–421
[CrossRef] | [PubMed]
 
Geddes  JR;  Lawrie  SM:  Obstetric complications and schizophrenia: a meta-analysis.  Br J Psychiatry 1995; 167:786–793
[CrossRef] | [PubMed]
 
Cannon  TD;  Yolken  R;  Buka  S;  Torrey  EF; Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders:  Decreased neurotrophic response to birth hypoxia in the etiology of schizophrenia.  Biol Psychiatry 2008; 64:797–802
[CrossRef] | [PubMed]
 
Nicodemus  KK;  Marenco  S;  Batten  AJ;  Vakkalanka  R;  Egan  MF;  Straub  RE;  Weinberger  DR:  Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk.  Mol Psychiatry 2008; 13:873–877
[CrossRef] | [PubMed]
 
Walker  EF:  Developmentally moderated expressions of the neuropathology underlying schizophrenia.  Schizophr Bull 1994; 20:453–480
[CrossRef] | [PubMed]
 
Done  DJ;  Crow  TJ;  Johnstone  EC;  Sacker  A:  Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11.  BMJ 1994; 309:699–703
[CrossRef] | [PubMed]
 
Davidson  M;  Reichenberg  A;  Rabinowitz  J;  Weiser  M;  Kaplan  Z;  Mark  M:  Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents.  Am J Psychiatry 1999; 156:1328–1335
[PubMed]
 
Woodberry  KA;  Giuliano  AJ;  Seidman  LJ:  Premorbid IQ in schizophrenia: a meta-analytic review.  Am J Psychiatry 2008; 165:579–587
[CrossRef] | [PubMed]
 
Lipska  BK;  Weinberger  DR:  Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat.  Brain Res Dev Brain Res 1993; 75:213–222
[CrossRef] | [PubMed]
 
Lodge  DJ;  Grace  AA:  Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia.  Behav Brain Res 2009b; 204:306–312
[CrossRef] | [PubMed]
 
Lavin  A;  Moore  HM;  Grace  AA:  Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats.  Neuropsychopharmacology 2005; 30:1426–1435
[CrossRef] | [PubMed]
 
Jaaro-Peled  H;  Hayashi-Takagi  A;  Seshadri  S;  Kamiya  A;  Brandon  NJ;  Sawa  A:  Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1.  Trends Neurosci 2009; 32:485–495
[CrossRef] | [PubMed]
 
Kleinman  JE;  Law  AJ;  Lipska  BK;  Hyde  TM;  Ellis  JK;  Harrison  PJ;  Weinberger  DR:  Genetic neuropathology of schizophrenia: new approaches to an old question and new uses for postmortem human brains.  Biol Psychiatry 2011; 69:140–145
[CrossRef] | [PubMed]
 
Nakata  K;  Lipska  BK;  Hyde  TM;  Ye  T;  Newburn  EN;  Morita  Y;  Vakkalanka  R;  Barenboim  M;  Sei  Y;  Weinberger  DR;  Kleinman  JE:  DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms.  Proc Natl Acad Sci USA 2009; 106:15873–15878
[CrossRef] | [PubMed]
 
Tan  W;  Wang  Y;  Gold  B;  Chen  J;  Dean  M;  Harrison  PJ;  Weinberger  DR;  Law  AJ:  Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia.  J Biol Chem 2007; 282:24343–24351
[CrossRef] | [PubMed]
 
Kao  WT;  Wang  Y;  Kleinman  JE;  Lipska  BK;  Hyde  TM;  Weinberger  DR;  Law  AJ:  Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain.  Proc Natl Acad Sci USA 2010; 107:15619–15624
[CrossRef] | [PubMed]
 
Hyde  TM;  Lipska  BK;  Ali  T;  Mathew  SV;  Law  AJ;  Metitiri  OE;  Straub  RE;  Ye  T;  Colantuoni  C;  Herman  MM;  Bigelow  LB;  Weinberger  DR;  Kleinman  JE:  Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.  J Neurosci 2011; 31:11088–11095
[CrossRef] | [PubMed]
 
Tao  R;  Cousijn  H;  Jaffe  AE;  Burnet  P;  Philip  WJ;  Edwards  F;  Eastwood  S;  Shin  JH;  Lane  T;  Walker  MA;  Maher  BJ;  Weinberger  DR;  Harrison  P;  Hyde  TM;  Kleinman  JE:  A novel transcript fetally regulated by the psychosis risk SNP rs1344706, and alterations in schizophrenia, bipolar disorder, and major depression.  JAMA Psychiatry (in press)
 
Huffaker  SJ;  Chen  J;  Nicodemus  KK;  Sambataro  F;  Yang  F;  Mattay  V;  Lipska  BK;  Hyde  TM;  Song  J;  Rujescu  D;  Giegling  I;  Mayilyan  K;  Proust  MJ;  Soghoyan  A;  Caforio  G;  Callicott  JH;  Bertolino  A;  Meyer-Lindenberg  A;  Chang  J;  Ji  Y;  Egan  MF;  Goldberg  TE;  Kleinman  JE;  Lu  B;  Weinberger  DR:  A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.  Nat Med 2009; 15:509–518
[CrossRef] | [PubMed]
 
Xu  B;  Ionita-Laza  I;  Roos  JL;  Boone  B;  Woodrick  S;  Sun  Y;  Levy  S;  Gogos  JA;  Karayiorgou  M:  De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia.  Nat Genet 2012; 44:1365–1369
[CrossRef] | [PubMed]
 
Gulsuner  S;  Walsh  T;  Watts  AC;  Lee  MK;  Thornton  AM;  Casadei  S;  Rippey  C;  Shahin  H;  Nimgaonkar  VL;  Go  RC;  Savage  RM;  Swerdlow  NR;  Gur  RE;  Braff  DL;  King  MC;  McClellan  JM; Consortium on the Genetics of Schizophrenia (COGS); PAARTNERS Study Group:  Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.  Cell 2013; 154:518–529
[CrossRef] | [PubMed]
 
Buka  SL;  Fan  AP:  Association of prenatal and perinatal complications with subsequent bipolar disorder and schizophrenia.  Schizophr Res 1999; 39:113–119, discussion 160–161
[CrossRef] | [PubMed]
 
Diagnostic and Statistical Manual of Mental Disorders
 
Johnson  MB;  Kawasawa  YI;  Mason  CE;  Krsnik  Z;  Coppola  G;  Bogdanović  D;  Geschwind  DH;  Mane  SM;  State  MW;  Sestan  N:  Functional and evolutionary insights into human brain development through global transcriptome analysis.  Neuron 2009; 62:494–509
[CrossRef] | [PubMed]
 
Kang  HJ;  Kawasawa  YI;  Cheng  F;  Zhu  Y;  Xu  X;  Li  M;  Sousa  AM;  Pletikos  M;  Meyer  KA;  Sedmak  G;  Guennel  T;  Shin  Y;  Johnson  MB;  Krsnik  Z;  Mayer  S;  Fertuzinhos  S;  Umlauf  S;  Lisgo  SN;  Vortmeyer  A;  Weinberger  DR;  Mane  S;  Hyde  TM;  Huttner  A;  Reimers  M;  Kleinman  JE;  Sestan  N:  Spatio-temporal transcriptome of the human brain.  Nature 2011; 478:483–489
[CrossRef] | [PubMed]
 
Colantuoni  C;  Lipska  BK;  Ye  T;  Hyde  TM;  Tao  R;  Leek  JT;  Colantuoni  EA;  Elkahloun  AG;  Herman  MM;  Weinberger  DR;  Kleinman  JE:  Temporal dynamics and genetic control of transcription in the human prefrontal cortex.  Nature 2011; 478:519–523
[CrossRef] | [PubMed]
 
Ripke  S,  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]
 
Ripke  S;  O'Dushlaine  C;  Chambert  K;  Moran  JL;  Kähler  AK;  Akterin  S;  Bergen  SE;  Collins  AL;  Crowley  JJ;  Fromer  M;  Kim  Y;  Lee  SH;  Magnusson  PK;  Sanchez  N;  Stahl  EA;  Williams  S;  Wray  NR;  Xia  K;  Bettella  F;  Borglum  AD;  Bulik-Sullivan  BK;  Cormican  P;  Craddock  N;  de Leeuw  C;  Durmishi  N;  Gill  M;  Golimbet  V;  Hamshere  ML;  Holmans  P;  Hougaard  DM;  Kendler  KS;  Lin  K;  Morris  DW;  Mors  O;  Mortensen  PB;  Neale  BM;  O'Neill  FA;  Owen  MJ;  Milovancevic  MP;  Posthuma  D;  Powell  J;  Richards  AL;  Riley  BP;  Ruderfer  D;  Rujescu  D;  Sigurdsson  E;  Silagadze  T;  Smit  AB;  Stefansson  H;  Steinberg  S;  Suvisaari  J;  Tosato  S;  Verhage  M;  Walters  JT;  Multicenter Genetic Studies of Schizophrenia Consortium;  Levinson  DF;  Gejman  PV;  Kendler  KS;  Laurent  C;  Mowry  BJ;  O'Donovan  MC;  Owen  MJ;  Pulver  AE;  Riley  BP;  Schwab  SG;  Wildenauer  DB;  Dudbridge  F;  Holmans  P;  Shi  J;  Albus  M;  Alexander  M;  Campion  D;  Cohen  D;  Dikeos  D;  Duan  J;  Eichhammer  P;  Godard  S;  Hansen  M;  Lerer  FB;  Liang  KY;  Maier  W;  Mallet  J;  Nertney  DA;  Nestadt  G;  Norton  N;  O'Neill  FA;  Papadimitriou  GN;  Ribble  R;  Sanders  AR;  Silverman  JM;  Walsh  D;  Williams  NM;  Wormley  B;  Psychosis Endophenotypes International Consortium;  Arranz  MJ;  Bakker  S;  Bender  S;  Bramon  E;  Collier  D;  Crespo-Facorro  B;  Hall  J;  Iyegbe  C;  Jablensky  A;  Kahn  RS;  Kalaydjieva  L;  Lawrie  S;  Lewis  CM;  Lin  K;  Linszen  DH;  Mata  I;  McIntosh  A;  Murray  RM;  Ophoff  RA;  Powell  J;  Rujescu  D;  Van Os  J;  Walshe  M;  Weisbrod  M;  Wiersma  D;  Wellcome Trust Case Control Consortium 2;  Donnelly  P;  Barroso  I;  Blackwell  JM;  Bramon  E;  Brown  MA;  Casas  JP;  Corvin  AP;  Deloukas  P;  Duncanson  A;  Jankowski  J;  Markus  HS;  Mathew  CG;  Palmer  CN;  Plomin  R;  Rautanen  A;  Sawcer  SJ;  Trembath  RC;  Viswanathan  AC;  Wood  NW;  Spencer  CC;  Band  G;  Bellenguez  C;  Freeman  C;  Hellenthal  G;  Giannoulatou  E;  Pirinen  M;  Pearson  RD;  Strange  A;  Su  Z;  Vukcevic  D;  Donnelly  P;  Langford  C;  Hunt  SE;  Edkins  S;  Gwilliam  R;  Blackburn  H;  Bumpstead  SJ;  Dronov  S;  Gillman  M;  Gray  E;  Hammond  N;  Jayakumar  A;  McCann  OT;  Liddle  J;  Potter  SC;  Ravindrarajah  R;  Ricketts  M;  Tashakkori-Ghanbaria  A;  Waller  MJ;  Weston  P;  Widaa  S;  Whittaker  P;  Barroso  I;  Deloukas  P;  Mathew  CG;  Blackwell  JM;  Brown  MA;  Corvin  AP;  McCarthy  MI;  Spencer  CC;  Bramon  E;  Corvin  AP;  O'Donovan  MC;  Stefansson  K;  Scolnick  E;  Purcell  S;  McCarroll  SA;  Sklar  P;  Hultman  CM;  Sullivan  PF:  Genome-wide association analysis identifies 13 new risk loci for schizophrenia.  Nat Genet 2013; 45:1150–1159
[CrossRef] | [PubMed]
 
Voineagu  I;  Wang  X;  Johnston  P;  Lowe  JK;  Tian  Y;  Horvath  S;  Mill  J;  Cantor  RM;  Blencowe  BJ;  Geschwind  DH:  Transcriptomic analysis of autistic brain reveals convergent molecular pathology.  Nature 2011; 474:380–384
[CrossRef] | [PubMed]
 
Allen Institute for Brain Science:  BrainSpan: Atlas of the Developing Human Brain, 2011. http://www.brainspan.org/
 
Kang  YH;  Galal  WC;  Farina  A;  Tappin  I;  Hurwitz  J:  Properties of the human Cdc45/Mcm2-7/GINS helicase complex and its action with DNA polymerase epsilon in rolling circle DNA synthesis.  Proc Natl Acad Sci USA 2012; 109:6042–6047
[CrossRef] | [PubMed]
 
Zhang  Z;  Sun  Y;  Cho  YW;  Chow  CC;  Simons  SS  Jr:  PA1 protein, a new competitive decelerator acting at more than one step to impede glucocorticoid receptor-mediated transactivation.  J Biol Chem 2013; 288:42–58
[CrossRef] | [PubMed]
 
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