Objective: This paper aims to summarise the latest molecular genetic findings in schizophrenia, while providing background information on a number of relevant methodological issues.
Method: Accumulative genetic data indicate that schizophrenia is a genetically complex disease with an unclear mode of transmission. The development and rapid progression of molecular genetics have provided a wide variety of methods to search for genes predisposing to human disease. The genetic basis for a number of the simpler diseases has been identified and characterised using these methods. More recently, progress has been made in identifying genes predisposing to the genetically more complex diseases such as diabetes mellitus, multiple sclerosis, bipolar disorder and schizophrenia.
Results: The latest findings on chromosomes 3, 6, 8, 13, 18 and 22 and on the chromosome are reviewed.
Conclusions: There is now suggestive support for three susceptibility loci (6p24–22, 8p22–21 and 22q12-q13.1) for schizophrenia, and it is likely that other regions will emerge from studies now in progress. Finding and then characterising genes within these loci will require long-term commitment and systematic efforts in clinical, laboratory and analytical fields.
TsuangMTGilbertsonMWFaraoneSVThe genetics of schizophrenia. Current knowledge and future directions. Schizophrenia Research1991; 4:157–171.
2.
KendlerKSMcGuireMGruenbergAMWalshD.Outcome and family study of the subtypes of schizophrenia in the west of Ireland. American Journal of Psychiatry1994; 151:849–856.
3.
KendlerKSTwin studies of schizophrenia: a current perspective. American Journal of Psychiatry1983; 140:1413–1425.
4.
KetySSSchizophrenic illness in the families of schizophrenic adoptees: findings from the Danish national sample. Schizophrenia Bulletin1988; 14:217–222.
5.
RischN.Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genetic Epidemiology1990; 7:3–16, 17–45.
6.
LevinsonDFMowryBJDefining the schizophrenic spectrum: issues for genetic linkage studies. Schizophrenia Bulletin1991; 17:491–514.
7.
MowryBJLevinsonDFGenetic linkage in schizophrenia: methods, recent findings and future directions. Australian and New Zealand Journal of Psychiatry1993; 27:200–218.
8.
MaierWLichtermannDMingesJContinuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study. Archives of General Psychiatry1993; 50:871–883.
9.
KendlerKSMcGuireMGruenbergAMSpellmanMO'HareAWalshD.The Roscommon Family Study. II. The risk of nonschizophrenic nonaffective psychoses in relatives. Archives of General Psychiatry1993; 50:645–652.
10.
KendlerKSMcGuireMGruenbergAMO'HareASpellmanMWalshD.The Roscommon Family Study. IV. Affective illness, anxiety disorders, and alcoholism in relatives. Archives of General Psychiatry1993; 50:952–960.
11.
SpitzerRJEndicottJRobinsE.Research diagnostic criteria for a selected group of functional disorders. New York: New York State Psychiatric Institute, 1978.
12.
KendlerKSGruenbergAMTsuangMTA DSM-III family study of the nonschizophrenic psychotic disorders. American Journal of Psychiatry1986; 143:1098–1105.
13.
GladisMMLevinsonDFMowryBJDelusions in schizophrenia spectrum disorders: diagnostic issues. Schizophrenia Bulletin1994; 20:747–754.
14.
WebbCTLevinsonDFSchizotypal and paranoid personality disorder in the relatives of patients with schizophrenia and affective disorders: a review. Schizophrenia Research1993; 11:81–92.
15.
GershonESde LisiLEHamovitJA controlled family study of chronic psychoses. Archives of General Psychiatry1988; 45:328–337.
16.
HolmansP.Asymptotic properties of affected-sib-pair linkage analysis. American Journal of Human Genetics1993; 52:362–374.
17.
HauserERBoehnkeMGuoSRischN.Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations. Genetic Epidemiology1996; 13:117–137.
18.
KruglyakLDalyMJReeve-DalyMPLanderESParametric and nonparametric linkage analysis: a unified multipoint approach. American Journal of Human Genetics1996; 58:1347–1363.
19.
WeeksDELangK.The affected-pedigree-member method of linkage analysis. American Journal of Human Genetics1988; 42:315–326.
20.
SandaAIFordJPGenomic analysis I: inheritance units and genetic selection in the rapid discovery of locus linked DNA markers. Nucleic Acids Research1986; 14:7265–7283.
21.
FalkDTRubinsteinP.Haplotype relative risks: an easy, reliable way to construct a proper control sample for risk calculations. Annals of Human Genetics1987; 51:227–233.
22.
TerwilligerJDOttJ.A haplotype-based haplotype relative risk statistic. Human Heredity1992; 42:337–346.
23.
SpielmanRSMcGinnisREEwensWJTransmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). American Journal of Human Genetics1993; 52:506–516.
24.
CardonLRSmithSDFulkerDWKimberlingWJPenningtonBFde FriesJCQuantitative trait locus for reading disability on chromosome 6. Science1994; 266:276–279.
25.
OttJ.Analysis of human genetic linkage. Baltimore: Johns Hopkins Press, 1991.
26.
LanderESKruglyakL.Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics1995; 11:241–247.
27.
BotsteinDWhiteRLSkolnickMDavisRWConstruction of a genetic linkage map in man using restriction fragment length polymorphisms. American Journal of Human Genetics1980; 32:314–331.
28.
SherringtonRBrynjolfssonJPeturssonHLocation of a susceptibility locus for schizophrenia on chromosome 5. Nature1988; 336:164–167.
29.
PulverAEKarayiorgouMWolyniecPSSequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1. American Journal of Medical Genetics1994; 54:36–43.
30.
PulverAEKarayiorgouMLasseterVKFollow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1: Part 2. American Journal of Medical Genetics1994; 54:44–50.
31.
PulverAESchizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. American Journal of Medical Genetics1995; 60:252–260.
32.
StraubREMacLeanCJO'NeillAFA potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity. Nature Genetics1995; 11:287–293.
33.
WildenauerDHallmayerJAlbusMA susceptibility locus for affective and schizophrenic disorder?Psychiatric Genetics1996; 6:152.
34.
CrowTJde LisiLELofthouseRAn examination of linkage of schizophrenia and schizoaffective disorder to the pseudoautosomal region (Xp22.3). British Journal of Psychiatry1994; 164:159–164.
35.
BassettASMcGillivrayBCJonesBDPantzarJTPartial trisomy chromosome 5 cosegregating with schizophrenia. Lancet1988; 1:799–801.
36.
KennedyJLGiuffraLAMoisesHWEvidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree. Nature1988; 336:167–170.
37.
ClairSt DMBlackwoodDMuirWNo linkage of chromosome 5q11-q13 markers to schizophrenia in Scottish pedigrees. Nature1989; 339:305–309.
38.
Detera-WadleighSDGoldinLRSherringtonRExclusion of linkage to 5q11–13 in families with schizophrenia and other psychiatric disorders. Nature1989; 340:391–393.
39.
KaufmannCAde LisiLELehnerTGilliamTCPhysical mapping and linkage analysis of a putative schizophrenia locus on chromosome 5q. Schizophrenia Bulletin1989; 15:441–452.
40.
AschauerHNAschauer-TreiberGIsenbergKENo evidence for linkage between chromosome 5 markers and schizophrenia. Human Heredity1990; 40:109–115.
41.
McGuffinPSargeantMHettiGTidmarshSWhatleySMarchbanksRMExclusion of a schizophrenia susceptibility gene from the chromosome 5q11-q13 region: new data and a reanalysis of previous reports. American Journal of Human Genetics1990; 47:524–535.
42.
CroweRRBlackDWWesnerRAndreasenNACookmanARobyJ.Lack of linkage to chromosome 5q11-q13 markers in six schizophrenia pedigrees. Archives of General Psychiatry1991; 48:357–361.
43.
CampionDD'AmatoTWaksmanGLinkage study of schizophrenia with chromosome 5 markers. Psychiatric Genetics1991; 2:14.
44.
HallmayerJMaierWAckenheilMEvidence against linkage of schizophrenia to chromosome 5q11-q13 markers in systematically ascertained families. Biological Psychiatry1992; 31:83–94.
45.
MacciardiFCavalliniMCKennedyJLTesting the hypothesis of genetic linkage between schizophrenia and dopamine receptor genes. Psychiatric Genetics1991; 2:17–18.
46.
HovattaISeppalaJPekkarinenPTanskanenALonnqvistJPeltonenL.Linkage analysis in two schizophrenic families originating from a restricted subpopulation of Finland. Psychiatric Genetics1994; 4:143–152.
47.
KarayiorgouMKaschLLasseterVKReport from the Maryland Epidemiology Schizophrenia Linkage Study: no evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model. American Journal of Medical Genetics1994; 54:345–353.
48.
MankooBSherringtonRBrynjolfssonJNew microsatellite polymorphisms provide a highly polymorphic map of chromosome 5 bands q11.2–q13.3 for linkage analysis of Icelandic and English families affected by schizophrenia. Psychiatric Genetics1991; 2:17.
49.
CollingeJde LisiLEBoccioAEvidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs. British Journal of Psychiatry1991; 158:624–629.
50.
de LisiLEDevotoMLofthouseRSearch for linkage to schizophrenia on the X and Y chromosomes. American Journal of Medical Genetics1994; 54:113–121.
51.
de LisiLEDevotoMLofthouseRShieldsGSmithACrowTJSearch for linkage to X and Y chromosomes in families with schizophrenia and schizoaffective disorder. Psychiatric Genetics1995; Suppl.:S51.
52.
CoonHHolikJHoffMAnalysis of chromosome 22 markers in nine schizophrenia pedigrees. American Journal of Medical Genetics1994; 54:72–79.
53.
ValladaHCurtisDShamPLinkage disequilibrium studies on chromosome 22. Psychiatric Genetics1995; Suppl.:S15.
54.
AlbusMZillPSchwabSGSibpair analysis reveals further evidence for a minor schizophrenia predisposing locus on chromosome 22q. Psychiatric Genetics1995; Suppl.:S12.
55.
MoisesHWYangLLiTPotential linkage disequilibrium between schizophrenia and locus D22S278 on the long arm of chromosome 22. American Journal of Medical Genetics1995; 60:465–467.
56.
SchwabSGLererBAlbusMPotental linkage for schizophrenia on chromosome 22q12-q13: a replication study. American Journal of Medical Genetics1995; 60:436–443.
PolymeropolousMHCoonHByerleyWSearch for a schizophrenia susceptibility locus on human chromosome 22. American Journal of Medical Genetics1994; 54:93–99.
59.
DanielsJKWilliamsNMWilliamsJNo evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol-O-methyltransferase activity. Psychiatric Genetics1995; Suppl.:S13.
60.
Schizophrenia Collaborative Linkage Group (chromosome 22).A meta-analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia. American Journal of Medical Genetics1996; 67:40–45.
61.
ShprintzenRJGoldbergRGolding-KushnerKJMarionRWLate-onset psychosis in the velo-cardio-facial syndrone. American Journal of Medical Genetics1992; 42:141–142.
62.
PulverAENestadtGGoldbergRPsychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. Journal of Nervous and Mental Disease1994; 182:476–478.
63.
Schizophrenia Collaborative Linkage Group for Chromosomes 3, 6 and 8.Additional support for schizophrenia linkage findings on chromosomes 6 and 8: a multicenter study. American Journal of Medical Genetics1996; 674:580–594.
64.
DiehlSRWangSDetera-WadleighSEvidence suggesting possible SCA1 gene involvement in schizophrenia. American Journal of Human Genetics1994; 55:867.
65.
AntonarakisSEBlouinJLPulverAESchizophrenia susceptibility and chromosome 6p24–22. Nature Genetics1995; 11:235–236.
66.
MoisesHWYangLKristbjarnarsonHAn international two-stage genome-wide search for schizophrenia susceptibility genes. Nature Genetics1995; 11:321–324.
67.
SchwabSGAlbusMHallmayerEvaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nature Genetics1995; 11:325–327.
68.
MowryBNancarrowDLennonDSchizophrenia susceptibility and chromosome 6p24–22. Nature Genetics1995; 11:233–234.
69.
GurlingHKalsiGHui-SuiChen ASchizophrenia susceptibility and chromosome 6p24–22. Nature Genetics1995; 11:234–235.
70.
RileyBPMogudi-CarterMRajagolpalanSJenkinsTWilliamsonR.No evidence for linkage of schizophrenia to the short arm of chromosome 6 in a sample of southern African Bantu-speaking families. Psychiatric Genetics1995; Suppl.:S34.
71.
CoonHMyles-WorsleyMWaldoMSegregation, linkage and linkage disequilibrium analysis of Micronesian schizophrenia families. Psychiatric Genetics1995; Suppl.:S49.
72.
SasakiTBassettASHonerWGEvaluation of markers at 6p21–23 in Eastern Canadian schizophrenia families. Psychiatric Genetics1995; Suppl.:S34.
73.
LinM-WCurtisDWilliamsNSuggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1–q32. Psychiatric Genetics1995; 5:117–126.
74.
AntonarakisSEBlouinJLCurranMLinkage and sib-pair analysis reveal a potential schizophrenia susceptibility gene on chromosome 13q32. Psychiatric Genetics1996; 6:136.
75.
CoonHJensenSHolikJGenomic scan for genes predisposing to schizophrenia. American Journal of Medical Genetics1994; 54:59–71.
76.
BarbeauA.Dopamine and mental function. In: MalitzS, ed. L-dopa and behavior. New York: Raven Press, 1972:9–33.
77.
FardeLHallHEhrinESedvallG.Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science1986; 231:258–261.
78.
SeemanPOharaKUlpianCSchizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2. Neuropsychopharmacology1993; 8:137–142.
DragoJGerfenCRLachowiczJEAltered striatal function in a mutant mouse lacking D1A dopamine receptors. Proceedings of the National Academy of Science USA1994; 91:12564–12568.
81.
ParkBHFishburnCSCarmonSAcciliDFuchsS.Structural organization of the murine D3 dopamine receptor gene. Journal of Neurochemistry1995; 64:482–486.
82.
EbsteinRPNovickOUmanskyRDopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nature Genetics1996; 12:78–80.
83.
BenjaminJLiLPattersonCGreenbergBDMurphyDLHamerDHPopulation and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nature Genetics1996; 12:81–84.