Genetic Linkage in Schizophrenia: Perspectives From Genetic Epidemiology

VOL. 15, NO. 3, 1989 Genetic Linkage inSchizophrenia:Perspectives From GeneticEpidemiology

by Matthew McGue andIrving I. Qottesman

Abstract

Research on the genetic epidemiol-ogy of schizophrenia is briefly andselectively reviewed. The followingthree salient features of schizo-phrenia that represent challenges tothe design of linkage studies areidentified: (1) The analysis of twinand family data has consistentlyfailed to identify a single majorgene effect upon schizophreniarisk; (2) the ascertainment of multi-plex families does not guaranteethe sampling of families who aresegregating for the major geneeven if a major gene effect exists;and (3) environmental influencesappear to play an essential role inthe etiology of at least some formsof schizophrenia. The implications •of these features for the design oflinkage studies in schizophreniaare discussed.

Identifying the genetic mechanismsthat underlie individual differencesin human behavior remains one ofthe most significant problems facingthe human geneticist. Progress hasbeen impeded by the complexity ofthe behavioral phenotype. It is littlewonder that the advent of theapplication of molecular geneticmethods to human behavior (Gur-ling 1986) and the recent successesin linking behavioral conditionsincluding affective psychoses (Ege-land et al. 1987), reading disability(Smith et al. 1983), Alzheimer's dis-ease (St. George-Hyslop et al. 1987),and schizophrenia (Sherrington etal. 1988) to specific regions of thegenome have given rise to muchoptimism. Clearly the race hasbegun to apply molecular genetictechniques to the study of humanbehavior. As behavioral geneticists,we have long been interested in the

way knowledge of a genetic influ-ence will bring about a betterunderstanding of the developmentof psychopathology and eventualrational intervention and even pre-vention. It is an especially appro-priate time to consider whetherbehavioral pathology is best treatedas other human genetic disorders(i.e., more grist for the humangeneticist's mill), or whether theunraveling of genetic influences onbehavior will require new andunique research approaches.

Throughout its development,behavioral genetics has relied heav-ily on the biometrical approach, theGaltonian paradigm. This approach,although statistically sophisticated,has been widely criticized for itsinability to characterize the mecha-nisms of genetic influence (e.g.,Vogel and Motulsky 1986). Over thepast 22 years, we have engaged inbiometrical analyses of schizo-phrenia twin and family data(Gottesman and Shields 1967; Raoet al. 1981; McGue et al. 1983,1986). Although we agree that theseanalyses do not allow us to identifythe underlying generic processes,we believe they do help us tounderstand the genetics of schizo-phrenia. Indeed, as the fieldembarks upon intensive moleculargeneric studies of schizophrenia,the results of our biometrical analy-ses may have implications for theprobable success of alternative strat-egies for identifying single geneeffects on schizophrenia. We con-sider those results and some oftheir implications here.

For definitions of technical terms, seeglossary on p. 366.

Reprint requests should be sent to Dr.M. McGue, Dept. of Psychology, Uni-versity of Minnesota, 75 East River Rd.,Minneapolis, MN 55455.

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454 SCHIZOPHRENIA BULLETIN

Genetic Epidemiology ofSchizophrenia

The most powerful and consistentpredictor of risk for schizophrenia isbeing an identical twin or first-degree relative of a schizophrenicpatient (Gottesman et al. 1982;Eaton 1985). Table 1 gives estimatedlifetime risks (i.e., age-correctedvalues) for developing schizo-phrenia among the relatives ofschizophrenic probands pooledfrom systematic studies undertakenin Western Europe since 1920 (for acomplete description of how thedata were compiled, see Slater andCowie [1971] and Gottesman et al.[1982]). Values for a broader defini-tion, including "probable schizo-phrenia," are about 25 percenthigher than those given in thetable. With the exception of thetwin data, where a large correlationin age at onset as well as continuedfollowup obviates the need, all riskshave been adjusted for variable ageof onset using variations of theWeinberg method (Gottesman et al.1982).

There is a strong associationbetween the magnitude of the riskin the relative and the degree of

genetic relationship to the proband.The most distinctive features of thisassociation are the monozygoric(MZ) twin concordance rate and therisk to the offspring of two schizo-phrenic parents, both of which arelarge relative to the risks amongother family members. The MZ rateis approximately five times the rateamong first-degree relatives, whichin turn is approximately 2lk timesthe rate among second-degTee rela-tives. The association betweenfamilial risk and proportion ofgenes shared with the index case isapproximated by an exponentialdecay function (figure 1). Alterna-tive hypotheses about the genetictransmission of schizophrenia aredistinguished by their ability toaccount for this essential epi-demiological association.

Twin, adoption, and family stud-ies are consistent in indicating thatthe familial aggregation of schizo-phrenia is accounted for largely, ifnot entirely, by genetic factors(Rosenthal 1972; McGue et al. 1986).Nonetheless, the MZ twin concord-ance rate is substantially less than100 percent, and thus (nonfamilial)environmental factors—be they pre-natal, perinatal, or sociocultural—

Table 1. Rates of definite schizophrenia among the relatives ofschizophrenic cases

Familial relationship

Offspring of 2 schizophrenic parentsMonozygotic twinsDizygotic twinsSiblingsOffspring of 1 schizophrenic parentHalf-siblingsNieces or nephewsGrandchildrenFirst cousinsSpouses

BZN<

134106149

75231678442

3965739

1600399

% Affected

36.644.312.17.39.42.92.72.81.61.0

'BZN gives the age-adjusted sample size (Gottesman et al. 1982)

play a significant role in the etiol-ogy of at least some forms ofschizophrenia. The existence ofenvironmental influences obscuresthe mechanism of generic transmis-sion, resulting in continued debateas to whether schizophrenia is asingle gene disorder, multifac-torially transmitted, or etiologicallyheterogeneous (Faraone and Tsuang1985). This is not a purely academicconcern, as the likelihood of identi-fying single gene effects on schizo-phrenia risk depends upon themode of transmission of thedisorder.

Single Gene Transmission

A prominent hypothesis (in fact,the first historically—Rosanoff andOrr 1911; Rudin 1916) for thegenetic basis of schizophrenia isthat it is a single gene defect (Book1953; Slater 1958; Heston 1970; Sla-ter and Cowie 1971; Matthysse etal. 1986). Under the so-called gener-alized single locus (GSL) model, thetransmission of schizophrenia isattributed solely to the segregationof two alleles (a schizophrenia-pro-moting allele, say A, and a non-schizophrenia-promohng allele, saya) at a single locus. Non-Mendelianfamilial risks are reconciled withsingle gene transmission by invok-ing reduced penetrance (i.e.,individuals who inherit at least onecopy of the disease-promoting genedo not necessarily develop the dis-order) and allowing for theexistence of sporadic cases (i.e.,individuals who inherit no copies ofthe disease-promoting gene but arestill at risk). Table 2 gives theparameterization of the GSL modelin terms of the frequency of theschizophrenia-promoting allele (a)and the penetrances of the threegenotypes ifAA,fM, and fj.



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VOL. 15", NO. 3, 1989 455

Figure 1. Lifetime morbid risks among the relatives of schizo-phrenic cases observed (empiric) and expected under amultifactorial threshold (MFT) model with 80% herltability and thegeneralized single locus model (GSL) proposed by Matthysse etal. 1986 as a function of proportion of genes shared with theproband

0.5 n

0.4-

0.3-

0.2-

0.1 -

0.0

MFT

GSL

. 2 5 . 1 2 5— , 1

1.0 -50

Proportion of GeneticOverlap

Proportion of genetic overlap Is 1 0 for monozygobc twins, 0.50 for first-degree relatives, 0 25 forhalf-siblings, and 0.125 for third-degree relatives.

Table 2. Parameterization of the generalized single locus model

GenotypeFrequencyPenetrance

AAq2

Aa2q(1-q)

(A.

aad-q)2

1..

Both the parsimony of the modeland the fact that a unitary genericetiology for schizophrenia would

enhance the promises of success formolecular genetic strategies makethe GSL model attractive. Nonethe-

less, the GSL model has repeatedlyfailed to account for the observedpattern of familial risk in schizo-phrenia (Elston and Campbell 1970;Kidd and Cavalli-Sforza 1973; Elstonet al. 1978; O'Rourke et al. 1982;Tsuang et al. 1982; Baron 1986;McGue et al. 1986). This failurestems directly from the inability ofthe GSL model to predict an expo-nential relationship between familialrisk and degree of the relationshipwith the proband.

James (1971) has shown how pre-cise quantitative predictions offamilial risks can be determinedunder a GSL model. The risk to rel-atives of a given class (KJ can beexpressed as a function of threeparameters derivable from the pen-etrances and gene frequency of theGSL model: the population preva-lence of the disorder (K„), theadditive genetic variance (Va), andthe dominance generic variance

Kr = Kp+ (1)

where \xj and \x2 are the proba-bilities that the proband and therelative share, respectively, one ortwo alleles at a locus identical bydescent.

In the absence of dominance (asappears to be the case for schizo-phrenia, where the risk to thesiblings is not greater than the riskto the offspring of a schizophrenicparent), predicted familial riskunder the GSL model is given by alinear function of proportion ofgenetic overlap between the relativeand the proband. That is, in theabsence of dominance, equation 1 isreduced to

Kr = Kp+ (I)

This linear prediction is in sharpcontrast to the observed exponentialrelationship. Along with theempiric risks, figure 1 plots thefamilial risks predicted by a recently



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proposed, and illustrative, GSLmodel of schizophrenia (Matthysseet al. 1986). The degree of reducedpenetrance required under a GSLmodel to account for the low famil-ial recurrence of schizophrenia isclearly inconsistent with the rela-tively large MZ twin concordancerate. In those cases where the GSLmodel did fit schizophrenia familydata, observations were made onlyon first-, second-, and third-degreerelatives, but not twins or the off-spring of dual matings (e.g.,Holzman et al. 1988). Study of fig-ure 1 shows that the linearrelationship between risk andshared genetic background pre-dicted by the GSL model holdsapproximately only for these classesof relatives.

Failure of the GSL model leadsnot only to rejection of simple sin-gle gene explanations for thetransmission of schizophrenia butalso to rejection of the hypothesisthat schizophrenia represents a het-erogeneous mixture of single genedisorders only. Suppose that therewere k different single gene defectseach of which give rise, with possi-bly reduced penetrance, toschizophrenia. Neglecting thoseexceedingly rare cases who inheritmore than one of these genes, thecomposite risk to a relative of aschizophrenic index case is a proba-bility weighted function of thatrelative's risk under each of the kseparate single gene models. Thatis, the composite familial risk, beingapproximated by a weighted aver-age of k separate linear functions,will also be a linear function of theproportion of genes shared with theproband.

A simple hypothetical exampleshould serve to illustrate. Supposethat the transmission of schizo-phrenia was due to two separatesingle gene defects either of which

alone could produce the disorder.The first is a rare completely pen-etrant (i.e., individuals who inheritat least one copy of the gene areaffected regardless of status at anyother locus) dominant gene with agene frequency of 0.002. The sec-ond is a common incompletelypenetrant gene with a frequency of0.03 and a penetrance vector of / / W

= 0.20,/A,, = 0.10 and fm = 0.201.Risks generated under such a het-erogeneity model are approximatelylinearly related to degree of geneticrelatedness between the probandand the relative. The expected MZconcordance rate is 0.391 (a valuenot that dissimilar from observedvalues), but the risk to the offspringof schizophrenic individuals is 0.201(a value clearly greater than thoseobserved). The failure of simple sin-gle gene models to account forschizophrenia family data compli-cates the search for single geneeffects. This failure does notexclude the possibility that schizo-phrenia may, in some cases, be dueto a rare highly penetrant geneeffect. Rather it excludes the pos-sibility that schizophrenia is aheterogeneous mixture of singlegene effects.

Multiple Gene Models

Multiple gene models do not sharethe empirical shortcomings of theGSL model. Although many alter-native multiple gene models havebeen proposed, we will focus uponthe two most widely applied—themultifactorial threshold (MFT) andmixed models. Under the MFTmodel, genetic factors are assumedto be polygenic. That is, a largenumber of genes, each of small andequal effect, combine additivelywith the effects of other genes andenvironmental factors to influenceschizophrenia liability. The qualita-

tive phenotype (here a diagnosis ofschizophrenia) is assumed to arisewhen an individual's combined lia-bility exceeds some threshold valuealong the unobserved liability con-tinuum (Falconer 1965; Gottesmanand Shields 1967).

The MFT model does an excellentjob in accounting for the distinctivepattern of familial risk in schizo-phrenia (McGue et al. 1983). Figure1 gives the predicted rates ofschizophrenia under an MFT modelthat attributes all familial transmis-sion to polygenic factors with amultifactorial heritabiliry of 80 per-cent, with the remaining 20 percentof the liability variance beingaccounted for by nonfamilialenvironmental effects (McGue et al.1985). Although the predicted MZconcordance rate is somewhat low,this model is statistically consistentwith the observed familial ratesand, more important, produces arisk function with the characteristicexponential decline.

Despite its predictive adequacy,there is a general reluctance toaccept the MFT model as an expla-nation for the transmission ofschizophrenia. This reluctancestems, perhaps, from the failure toidentify specific genetic andenvironmental contributors to theassumed multifactorial liability.Additionally, strict polygenic inheri-tance (i.e., many genes all of smalleffect) would likely preclude, forthe near future, attempts at identi-fying single gene effects onschizophrenia risk through molecu-lar genetic approaches. However,the fit of the MFT model does notpreclude (1) the existence of a sin-gle major gene whose effect uponschizophrenia risk is large relativeto the effects of other (poly)genes,(2) the possibility of rare singlegene disorders that give rise toschizophrenia, or (3) a tractable



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VOL. 15, NO. 3, 1989 457

MFT model of a limited number ofpolygenes (3, 4, or 5) each with a"subcomponent effect" on schizo-phrenia (cf. Wright 1934; Thoday1967). Molecular genetic strategiescould, presumably, be tailored foreach of these possibilities.

Meehl (1972a, 1972b) was the firstto suggest that both a major geneand polygenes play a role in theetiology of schizophrenia. UnderMeehl's theory, inheritance of asingle gene gives rise to a neuralintegrative deficit termed schizo-taxia that is expressed at thepersonality level as schizotypy.Expression of clinical schizophreniaamong individuals who inherit thesingle gene defect is postulated tobe a function of status on a host ofpolygenicly and environmentallyinfluenced potentiators includinganxiety, anhedonia, and socialintroversion.

The type of model proposed byMeehl has been termed the mixed(i.e., mixed major and polygenes)model by the human geneticistsMorton and MacLean (1974), whoalso developed analytical proce-dures for fitting the model to familydata. Although the procedures out-lined by Morton and MacLean canbe used, in theory, to identifymajor gene effects against a poly-genic background, in practice, theanalysis of qualitative family dataunder the mixed model has yieldedequivocal results. There have beenthree mixed model analyses ofschizophrenia family data (Carterand Chung 1980; Risch and Baron1984; Vogler et al., in press). In allthree cases the multifactorial modelthat included only polygenic effectscould not be rejected in favor of amixed model that included both asingle major gene and polygeniceffects. This failure may result froma lack of statistical power or to anabsence of a single major geneeffect on schizophrenia. With the

given data, it is difficult to resolvethe choice between these two pos-sibilities, although the repeatedfailure to identify single major geneeffects on schizophrenia despite rel-atively large family studies suggeststhat if single gene effects exist theymay be of modest magnitude only.

Simulation Studies

To identify the characteristics ofmixed single gene/polygene modelsthat generate accurate predictions offamilial risk, we recently completeda simulation study (Gottesman andMcGue, in press). In that study,familial risks under 275 differentmodels were computed and com-pared with observed schizophreniarisks. Family data were generatedunder a general model that allowedfor the following three additive con-tributors to schizophrenia liability:(1) a major gene component withtwo alleles (A and „) at a singlelocus in Hardy-Weinberg equilib-rium, (2) an additional polygeniccomponent that was assumed to benormally distributed with a con-stant variance for the threegenotypes (M, ^, and „„), and (3)a nonfamilial environmental compo-nent, also assumed to be normallydistributed with a constant vari-ance.' Familial environmental effects,for which there is little empiricalevidence (McGue et al. 1985), werenot modeled in the simulation. Thepenetrances of the three genotypeswere ordered according tofAA^Aa^aa ™th t h e heterozygotepenetrance, f/^, constrained toequal the average of the pen-etrances of the two homozygotes asis expected when there is no domi-nance variance at the single locus.In all cases, the lifetime prevalenceof schizophrenia was fixed at 1.0percent.

Familial risks were functions of

the following three (input) param-eters: (1) / ^ , the penetrance of themost frequently affected genotype;(2) s, the percentage of schizo-phrenic cases who do not have anycopies of the "schizophrenia gene"(i.e., the proportion of schizo-phrenic cases with the aa genotype,termed the proportion of sporadiccases); and (3) h2, the residual poly-genic heritability (i.e., the propor-tion of liability variance due topolygenic factors after the majorgene effect has been partialled out).Table 3 gives illustrative findingsfrom these simulations. Three gen-eral conclusions were drawn:

1. When the penetrance of themost frequently affected genotypewas high (fAA 3= equal to 0.4), pre-dicted familial risks wereinconsistent with observed risksunless both the percentage ofschizophenic cases without themajor gene was high (s ^ 0.60) andthe residual heritability was large(h2 =* 0.60). Put another way, if thereexists a single highly penetrantmajor gene for schizophrenia, sim-ulations of family data suggest thatfew schizophrenic cases possess it.This is illustrated in table 3 by thecomparison of the three inconsist-ent models numbered 5, 6, and 7with the consistent model num-bered 2.

2. When the penetrance of themost frequently affected genotypewas low (fAA =s 0.2), predicted famil-ial risks were inconsistent withobserved risks unless the residualheritability was large (h2 s= 0.60). Putanother way, a low-penetrant geneis consistent with schizophreniafamily data only when there is alsoa substantial polygenic effect. Thisis illustrated in table 3 by the twoconsistent models numbered 1 and3 and the two inconsistent modelsnumbered 8 and 9.

3. A pure MFT model with large



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heritability (h2 = 0.80) yields famil-ial risks consistent with observedrisks. This is illustrated by the con-sistent model numbered 4 intable 3.

These simulations suggest thatthree alternative classes of geneticmodels are consistent with thegeneric epidemiology of schizo-phrenia: (1) a heterogeneity-likemodel where the minority ofschizophrenic individuals inherit ahighly penetrant. but low frequencygene (the gene frequency for modelnumber 2 was 0.018), while themajority are affected because ofhigh multifactorial loading; (2) agene of modest-effect model wherea low penetrance (about 10 per-cent), moderately prevalent (genefrequency for model 3 was 0.097)gene contributes along with a siz-

able multifactorial component toschizophrenia risk; (3) a pure MFTmodel. Any one of these modelscould account for the failure ofmixed model analyses of schizo-phrenia family data to identify asingle major gene effect.

Ascertainment Strategies

The results of our simulations sug-gest that the existence of a singlemajor gene effect is not inconsistentwith the observed schizophreniafamily data, although the magni-tude of this effect on overall riskmay not be great. If a single majorgene exists, the question remains asto how best to sample pedigrees offamilies for linkage studies that areinformative with respect to themajor gene. One popular, and

seemingly sensible, strategy foridentifying families for intensivemolecular genetic study is to sam-ple "loaded pedigrees" (i.e., so-called multiplex families with alarge number of affected individ-uals). We were interested indetermining, for the four modelsfound to generate risk rates consist-ent with the observed familial rates,the extent to which (1) families withmultiple affected members areexpected to occur and (2) multiplexascertainment schemes succeed inenriching the sample with familiesthat are segregating for the majorgene.

For each of the four models,50,000 nuclear families consisting ofan index member (not necessarilyaffected) and possibly a spouse andup to 10 children were generated

Table 3. Illustrative results from the mixed model simulation of schizophrenia

Input

#

parameters

fAA S

Model

Major

Derived parameters% total variance of

gene Polygene Environment

Predicted risksto relatives of

schizophrenic cases ('

MZ 1st 2nd

%)

3rd

Consistent models

1234

0.100.600.100.00

0.800.800.0251.0

0.800.800.600.80

2.22.3

32.90.0

78.378.240.380.0

19.519.527.820.0

41.345.143.638.3

9.311.610.88.6

3.64.74.13.3

2.02.62.21.9

Inconsistent models

56789

0.600.600.600.100.10

0.600.050.050.0250.80

0.200.600.200.400.40

4.918.918.932.92.2

19.048.716.226.839.1

76.132.464.940.358.7

17.159.237.824.910.5

8.122.017.27.64.0

4.39.88.63.32.1

2.65.04.72.01.5

Note.—lu Is the penetrance of the most frequently affected genotype, s is the proportion of schizophrenic cases who do not carry the major gene, and tyis the residual multifactorial heritability. MZ = monozygotic twin; 1st - first-degree relative,' 2nd = second-degree relative; 3rd - third-degree relative.Table from Gottesmann 4 McGue (in press).



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VOL. 15, NO. 3, 1989 459

according to the parameters of thatmodel. Probability of marriage andnumber of offspring were chosen toreflect demographic features of theU.S. adult population. No adjust-ment was made for the reduction infertility known to be associatedwith schizophrenia (Erlenmeyer-Kimling 1978; Vogel 1979; 0degard1980). Average number of offspringwas 2.22 (SD = 1.4, range = 0-6.

Table 4 gives the distribution ofnumber of affected individualsamong families with at least oneaffected member. Two features oftable 4 warrant comment: (1) AUfour models predict that in a largepercentage of cases schizophrenicpatients will be the only affectedmembers of their nuclear family.This prediction is in accord with thedistribution of number of affectedfamily members observed in largefamily studies (e.g., Lindelius 1970).(2) Although rare, pedigTees withmultiple affected members areexpected under all four models oftransmission. Although expectedunder highly penetrant single genetransmission, the observation,especially under uncertain ascer-tainment, of loaded pedigrees doesnot allow unequivocal inference ofmode of transmission. Indeed, ofthe total of 200,000 nuclear familiesgenerated, only two contained as

many as five affected members.One family was generated undermodel number 3, a mixed modelwith high multifactorial heritability,and the other under model number4, a pure MFT model.

Table 5 gives the sample propor-tions of (1) affected individuals whocarry no copies of the schizo-phrenia-promoting gene (P[G-/S + ])and (2) normal individuals whocarry at least one copy of theschizophrenia-promoting gene(P[G + /S-]) under alternative sam-pling schemes for each of the threemodels for which there is a majorgene effect. These proportions canbe interpreted loosely as error ratesunder the alternative ascertainmentschemes; that is, the chance that anaffected individual in the sampledoes not have the gene and thechance that a normal individualdoes. As is evident from table 5,multiplex sampling strategies arenot necessarily expected to enrichthe sample for schizophrenic casespossessing the gene under any ofthe three models. Only for model 3,where the gene frequency is highbut the penetrance low, are mostsampled families expected to besegregating the major gene. None-theless, in this case a significantproportion of unaffected individualsalso possess the gene, and this

"false positive" rate is notimproved through multiplexsampling.

Role of the Environment

The existence of environmentallyinduced schizophrenic-like condi-tions (Davison 1987) as well as MZtwin concordance rates substantiallyless than 100 percent, prompts thequestion: Is the influence of theenvironment on schizophrenia dueprimarily to environmentallyinduced phenocopies of the disor-der, or is it that environmentaleffects combine multifactorially withan underlying genetic diathesis? Wenote that the popular distinctionbetween sporadic and familial formsof psychopathology presumes that amajor role of the environment is toinduce nontransmitted forms of thedisorder (see, however, Eaves et al.[1986] for a critical evaluation of thisdistinction as applied in geneticepidemiology).

Gottesman and Bertelsen (inpress) evaluated schizophrenia riskamong the offspring of Fischer'sconcordant and discordant twins.Relatively low rates of schizo-phrenia are expected among theoffspring of discordant MZ twins ifdiscordance among the geneticallyidentical parents is due largely to

Table 4. Distribution of number of affected nuclear family members under 4 alternative models forschizophrenia

ModeInput

#

1234

1parameters

0.100.600.100.00

s

0.800.800.0251.0

h2

0.800.800.600.80

1

1156 (0.912)1133(0.909)1311 (0.894)1214(0.918)

Number (%) ofmembers

2

97 (0.076)99 (0.079)

112(0.085)88 (0.067)

affected familyper family

3

14 (0.011)12(0.010)24 (0.018)17(0.013)

5=4

1 (0.001)3 (0.002)3 (0.003)4 (0.003)

Total1

1268124713111323

Note.—See note to table 3 for abbreviations.'Total gives the total number of nudear families, out of the 50,000 generated, with at least 1 schizophrenic member.



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Table 5. Proportion of schizophrenic cases without the major gene (P[G-/S + J) and proportion ofnormals with the major gene (P[G+/S-] ) under 3 alternative ascertainment schemes

#Affectedfamilymembers

Model #1 Model #2 Model #3

P(G-/S + ) P(G+/S-) P(G-/S + ) P(G+/S-) P(G-/S + ) P(G + /S-)

3= 15* 22= 3

0.7480.6580.652

0.0890.0890.028

0.8790.7890.542

0.0350.0540.125

0.0260.0000.000

0.4800.4270.516

environmentally induced pheno-copies. Table 6 gives the essentialfindings from this study. Althoughthe small sample allows only pre-liminary and cautiously drawnconclusions, the pattern of offspringrisk is striking. For the discordantMZ twins, the rate of schizo-phrenia-like psychosis is similaramong the offspring of the affectedand the unaffected twins, and bothrates are comparable to the overallrisk to the offspring of a schizo-phrenic parent (table 1). In contrast,for the discordant DZ twins, therate of schizophrenia-like psychosisis significantly higher among theoffspring of the affected twin thanamong the offspring of the unaf-fected twin. Furthermore, the rate

among the offspring of the effectedDZ twins is comparable to the rateamong the offspring of schizo-phrenic patients, while the rateamong the offspring of theunaffected cotwins is comparable tothe risk among the second-degreerelatives of schizophrenic patients(table 1).

These data suggest that the dis-cordance among the MZ twinscannot be attributed wholly to theexistence of nontransmissible formsof schizophrenia. Apparently, theexpression of schizophreniadepended upon both an inheritedgenetic diathesis, which was trans-mitted regardless of whether thediathesis was phenotypicallyexpressed, and exposure to

Table 6. Schizophrenia and schizophrenla-IIke psychosis in off-spring of discordant twins

Parent status

Monozygotlc sample

Affected twinUnaffected twin

Dizygotlc sample

Affected twinUnaffected twin

Number

1424

1352

Affected

14

11

MR%

10.0±9.017.4 + 7.7

8.3 + 7.62.1+2.1

Atofe.—Affected gives the total number of offspring affected with either schizophrenia or a schizo-phrenic-like psychosis. MR gives the estimated lifetime morbid risk using the Kaplan-Metor age-correction procedures. Table from Qottesman and Bertelsen (In press).

environmental stressors, to whichthe twins are differentially exposed.The possibility that the expressionof schizophrenia might dependupon exposure to requisite environ-mental triggers would seem tocomplicate, but certainly not pre-clude, genetic linkage studies whichare highly sensitive to the existenceof "false negatives" in the family.

Discussion and Conclusion

Alternative approaches to identify-ing single major gene effects onschizophrenia will be constrained,encouraged, or defeated by salientfeatures of the genetic epidemiologyof this complex disorder. Here wereviewed three such features, all ofwhich have significant implicationsfor designing linkage studies ofschizophrenia.

1. Nobody has ever been able todemonstrate statistically that a sin-gle major gene accounts for a largeshare of the overall risk for schizo-phrenia. We suggest that thisreflects more about the nature ofthis complex disorder than it doesabout limitations in the statisticalprocedures. Approaches premisedupon the hypothesis that schizo-phrenia is a unitary single genedisorder run counter to a vastamount of empirical research thatsuggests otherwise. At the least,



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VOL. 15, NO. 3, 1989 461

such approaches need to be justi-fied relative to their more em-pirically attractive alternatives.

Single gene effects on schizo-phrenia risk may exist. Oursimulations suggest that if they do,they are likely to be the result ofeither a highly prevalent gene witha very low penetrance or a very lowprevalent gene with a high pen-etrance. In either case, thecontribution to overall schizo-phrenia risk is modest. Forexample, Huntington's disease(HD) is often misdiagnosed as para-noid schizophrenia; about 20percent of HD cases present withparanoid schizophrenic phenotypes.HD is quite rare in the populationwith an incidence of 5 per 100,000.From the careful total populationstudy in southern Sweden byEssen-Moller et al. (1956) that usedindepth interviews by psychiatristswith every inhabitant, we obtain alifetime risk of 139 per 10,000 forschizophrenia. We can now answerthe question, what proportion ofschizophrenia-like psychoses areactually caused by what we nowknow to be a mutated dominantgene on chromosome 4 leading toHD? The answer is found by divid-ing the two population values or5/100,000 by 139/10,000 and thentaking 20 percent to get those HDcases who are, in this instance,"genocopies" of schizophrenia. Theresult of the calculations is that 7 in10,000 schizophrenic cases have this"major gene for schizophrenia-likepsychosis" and the gene would beidentified by studying such specialpedigrees with restriction fragmentlength polymorphisms (RFLPs) anda lucky choice of chromosome 4 asa starting place.

2. Ascertainment schemes aimedonly at identifying "loaded ped-igrees" may be useful, but thenagain they may not. Obviously,

linkage studies require loaded ped-igrees to provide powerful tests for -single gene effects. Nonetheless,multiplex families are expectedunder GSL and MFT transmission.This may leave the molecular genet-icist somewhat uneasy in claimingthat the family he or she is expend-ing great effort on happens to be a 'family segregating for the majorgene. It is notable in this regardthat the linkage studies for mentaldisorder that are currently available,whether for schizophrenia or affec-tive psychoses, were conductedwithout defining a sampling frame-work. We have no way of knowinghow many families in the generalpopulation were, in effect, screenedto find the interesting multiplexfamilies used to obtain the signifi-cant lod scores. Under suchconditions, the linkage studiesresemble the important data avail-able from individual case historiesprovided by such pioneers asFreud, Kraepelin, and E. Bleuler.As such, pedigrees with impressivelod scores as well as seminal casehistories can serve as hypothesis-generating sources but not as suffi-cient proof of etiology.

3. Environmental influences playan essential role in the etiology ofschizophrenia. In the rush tomolecular biology, it would appearshortsighted for psychopathologistsno longer to consider why it is thatamong two individuals, both ofwhom inherit a genetic diathesis,one will go on to develop the disor-der while the other will not. Itwould seem that progress will bemaximized by tying moleculargenetic approaches to furtherinquiry into environmentalinfluence.

The simulation results, as well asempirical data, suggest that linkagestudies of schizophrenia that areonly fishing expeditions may yield

few successes. An attractive alterna-tive, broadly supported by ourresearch, is the targeted strategy ofthe candidate gene approach (Gur-ling 1986). Wright (1934) andThoday (1967) have shown how amultifactorial system can be decom-posed into a small and tractablenumber of single gene effects (say,3, 4, or 5). Lander and Botstein(1988) have developed linkage anal-ysis methods that can be used withsuch systems in experimentallybred species. Appropriate strategiesin humans may be forthcoming.Likely sources for candidate geneswould be single gene effects uponthe many correlates of schizo-phrenia including D2 dopaminereceptors (Wong et al. 1986), cere-bral blood flow assessed withpositron emission tomography(Early et al. 1987), cerebral ventriclesize (Reveley et al. 1984), andsmooth pursuit eye tracking (Iaconoet al. 1981; Holzman et al. 1988).

Research on the genetic epi-demiology of schizophreniasuggests that it is a highly complexgenetic disorder whose precisemechanisms of transmissionremains uncertain. This will hardlycome as a revelation to anyone. Thepathway from gene product tobehavioral expression is obviouslylong and presumably providesmany opportunities for environ-mental modulation as well asmoderation by other biological,physiological, and behavioral sys-tems. The transmission ofschizophrenia appears whollyunlike the transmission of HD andcystic fibrosis. Coronary heart dis-ease and diabetes may representmore appropriate models fordesigning linkage studies of schizo-phrenia. The challenge thatpsychopathology presents to thegeneticist is not so much in findingmultiplex families that can be inten-



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sively studied but, rather, inadapting approaches that haveproved useful with relatively simplemedical genetic disorders to accountfor the complexities, heterogeneity,and environmental sensitivity ofhuman behavior.

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Acknowledgments

This study was supported in partby USPHS grant RR01632 from the

National Institutes of Health. Theauthors would like to thank MichaelGoay for his assistance in generat-ing the family data used in thesimulations.

The Authors

Matthew McGue, Ph.D., is Associ-ate Professor, Departments ofPsychology and Genetics, Univer-

sity of Minnesota, Minneapolis,MN. Irving 1. Gottesman, Ph.D.,F.R.C. Psych. Hon., is Professor ofPsychology, Department of Psy-chology, University of Virginia,Charlottesville, VA.

Announcement The New York State PsychiatricAssociation is sponsoring a sym-posium entitled "Coping With theTreatment Refractory Schizo-phrenic Patient" scheduled forSaturday, November 4, 1989, at theRoosevelt Hotel, New York, NY.

The symposium will address thechallenges that occur in the hospi-tals, the streets, within the family,and the special problems that resultfrom concurrent substance abuseand from violence.

For further information contact:

Lester E. ShapiroGeneral ChairmanJoint Committee on

Schizophrenia43 Andover RoadRockville Centre, NY 11570(516) 766-3442



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Genetic Linkage in Schizophrenia: Perspectives From Genetic Epidemiology

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