404 The Genetics ofSchizophrenia: A Review

by Seymour Kessler Abstract

The evidence suggesting that geneticfactors are involved in the etiologyof schizophrenia is reviewed. De-spite methodological and other dif-ficulties, independent lines ofresearch—family, twin, and adop-tion studies—point in a common di-rection: Persons genetically at riskfor schizophrenia are more likely tobecome affected than those who arenot. Current attempts to understandthe mode of inheritance of the geneor genes involved have become in-creasingly sophisticated and, con-sequently, less accessible (and pos-sibly useful) to clinicians andnongeneticist researchers.Guidelines are provided for the pro-vision of genetic counseling to af-fected persons and their relatives.Such counseling is frequently en-meshed with multiple psychosocial(rather than strictly medical) issuesand should be provided by profes-sionals with appropriate trainingand experience in psychotherapy.

Four years ago, the Schizophrenia Bul-letin published a critical review of theevidence bearing on the genetics ofschizophrenia. The review, writtenby two eminent psychiatric geneti-cists, Irving Gottesman and JamesShields, was accompanied by a set ofarticles which were to serve as com-mentaries on the Gottesman-Shieldsreview—clarifying/ refining, andelucidating. The review proved to beprovocative as well as informative,and the responses and discussionthat it evoked displayed an unusualdegree of underlying hypersensitiv-ity. In the ensuing exchanges, thepolarization of the old nature-nurture conflict reemerged in fullstrength. It was as if workers in thefield hSd undergone a mass regres-sion (Kessler 1976).

In retrospect, I realize that thetendencies of polarization andregression are inherent within thevery subject matter about which weare concerned. Schizophreniatouches us in very personal ways inour struggles to understand its na-ture and etiology. Its mystery andelusiveness attract us to any sign ofcertainty or glimmer of understand-ing, be it biochemical or psy-chodynamic. Thus, possibilitiesand hypotheses quickly becomedogmas. Also, as schizophrenicfamilies are marked by disturbancesof communication, perhaps we too,students and researchers of schizo-phrenia, are not immune to communi-cation difficulties among ourselves.No wonder then, humor is mistakenfor hostility and irony read as ire.

With these thoughts as a pream-ble, I will move on and attempt toreview briefly here the pertinent con-temporary evidence suggesting thatgenetic factors contribute to theetiology of schizophrenia. I then planto comment on some recent lines ofresearch pertinent to genetic investi-gations of schizophrenia, and lastly, Iwill address myself to some of theissues present in the genetic counsel-ing of this disorder. No attempt willbe made to be totally comprehensive,and the reader desiring a more thor-ough overview should consult Ro-senthal (1970), Slater and Cowie(1971), Gottesman and Shields(1976), and other appropriate re-views of the literature.

There are three major lines of evi-dence implicating a genetic involve-ment in the etiology of schizo-phrenia: family studies, twin studies,

Reprint requests should be addressedto Dr. Kessler, Genetic Counseling Pro-gram, Health and Medical Sciences Pro-gram, Bldg. 1-7, University of California,Berkeley, CA 94720.

VOL 6, NO. 3, 1980 405

and adoption studies. Each will bediscussed in turn.

Family Studies

The family study method is based onthe observation that genetic disor-ders show a familial concentration.Relatives of a proband or index caseshare a greater proportion of theirgenes in common than unrelatedpersons. Thus, to the extent that adisorder is genetically determined,relatives of affected individuals aremore likely to have inherited thepredisposing gene or genes than per-sons in the general population. Acommon strategy in human geneticstudies, then, is to compare theprevalence of the disorder among rel-atives of affected persons to the baserate of the disorder in the generalpopulation. If the rate of the disorderamong the former is significantlyhigher than among the latter, agenetic contribution to the etiology ofthe disorder is suspected. Furtherstudy of specific pedigrees frequentlyreveals information on the mode oftransmission of the gene or genes in-volved. Thus, a disorder whichshows a pattern of transmission fromunaffected mothers to one-half oftheir sons suggests that an X-linkedmode of inheritance is involved; apattern involving affected parentswith affected children is suggestiveof a dominant mode of transmission,and when groups of unaffected par-ents have one-quarter of their chil-dren affected, a recessive mode oftransmission is suggested. Thesetraits or disorders are the ones thatfollow relatively simple, Mendelianpatterns of inheritance and yieldpredictable ratios of affected tononaffected progeny in specifiedkinds of matings. As we shall see,schizophrenia does not fall into thiscategory.

Many studies have been carriedout worldwide to determine the inci-dence rate of schizophrenia in thegeneral population. The rates foundrange from 0.35 to 2.85 percent, witha mean around 0.85 percent. Thismean is a widely accepted base rateof schizophrenia in the general popu-lation in the United States and inEuropean countries. The differencesbetween various countries with re-spect to the incidence of schizo-phrenia may reflect changes in diag-nostic criteria, sampling biases,and/or varying psychosocial andother environmental conditions pre-disposing to schizophrenia. It is alsoconceivable that the different popula-tions represent differing gene pools,and hence differential frequencies ofthe gene or genes predisposing toschizophrenia.

The frequency of schizophreniaamong different classes of relatives ofprobands is shown in table 1. Thetable shows the pertinent data ascompiled by two different inves-tigators in the field, Rosenthal (1970)in the United States, and Slater a'ndCowie (1971) working in Great Bri-tain. The former tends to use medianvalues whereas the latter inves-tigators favor means. Irrespective ofthe method of averaging used, theresults are quite similar for any givendegree of relation to an index case.Thus the risk for a sib of an affectedindividual, given that neither parentis affected, ranges from 6.7 to 8.2percent. When one parent is af-fected, the risk rises to between 12.5and 13.8 percent.

Examination of table 1 reveals thatfor all close relatives of an index case,the risk for schizophrenia is de-cidedly higher than that for indi-viduals in the general population; therates vary from between 2 and 46times higher than the average risk forschizophrenia in the population.

Among first-degree relatives of aproband, the average risk forschizophrenia is roughly between 8and 10 percent. The risks for relativesare also graded so that relatives whoshare relatively less of their genes incommon with an affected individualshow a lower expectancy forschizophrenia than those who sharemore of their genes in common.Thus, overall, first-degree relativesshow higher risks for schizophreniathan second-degree relatives and thelatter, taking into consideration someamount of sampling error, appear toshow a higher risk for schizophreniathan their third-degree relatives.This distribution of risks among rela-tives of affected individuals is consist-ent with a genetic hypothesis. Alsoconsistent is the fact that the risk forschizophrenia increases as the ge-netic loading increases; children, bothof whose parents are affected, show adecidedly higher risk than those withonly one affected parent.

An apparently consistent findingamong first-degree relatives ofschizophrenic probands is that sibsand children seem to have a higherrisk for schizophrenia than do par-ents. This phenomenon has beenfound in several different studies,and the reasons for it are not entirelyclear. Rosenthal (1970) has specu-lated that multiple factors may affectthe self-selection for parenthood ofpreschizophrenic individuals. Theseinclude the ability to find and holdemployment, assume marital re-sponsibilities, sex drive, socio-economic, cultural, personality, andother variables.

Twin Studies

Another classical line of approachused to demonstrate generic in-volvement in the etiology ofschizophrenia is the twin method.

406 SCHIZOPHRENIA BULLETIN

Table 1. Estimates of the risk for schizophrenia among relatives ofschizophrenics (%)

ParentsSibs (neither parent affected)Sibs (one parent affected)All sibsChildrenChildren (both parents affected)Half-sibsAunts and unclesNephews and niecesGrandchildrenFirst cousins

Rosenthal (1970)

4.26.7

12.57.59.7

35.01

—1.72.32.61.7

Slater and Cowie(1971)

4.48.2

13.88.5

12.336.6^6.3

3.22.02.32.82.9

'Excludes KaHmann'8 (1938) study.

This method is based on the observa-tion that there are two classes oftwins, monozygotic (MZ) and di-zygotic (DZ) twins; identical andfraternal twins, respectively. Theformer derive from a single fertilizedovum, whereas the latter result fromtwo separate fertilizations. MZ twinsare genetically alike, whereas DZtwins are no more genetically alikethan ordinary siblings. If a disorder isgenetically determined, then onemight expect that pairs of MZ twinswould show significantly higher con-cordance rates than pairs of DZtwins.

Nearly a dozen major twin studiesof schizophrenia have been carriedout worldwide, and all show higherrates of concordance among MZ thanDZ twin pairs. In the studies carriedout before 1965, MZ concordancerates are 60 percent or more, whereasin those conducted since that time,average MZ concordance rates tendto be lower. These differences proba-bly reflect changing diagnostic stylesand variations in sampling and statis-tical procedures. The older studiesgenerally involved chronically af-fected resident hospital populations,

whereas the more recent studies,summarized in table 2, employedconsecutive admissions or datagathered from birth registers.

Concofdance rates may be calcu-lated in one of several ways. Table 2shows the results of two commonmethods of determining concor-dance, the pairwise and the pro-bandwise methods. In the pairwisemethod, one calculates the propor-tion of all pairs in which both twinsare affected, whereas in the lattermethod, the concordance rate isbased on'independently ascertainedaffected twins. Since members of anygiven pair of twins might be countedtwice using the proband method,concordance rates calculated thisway tend to be higher than those ofthe pairwise method. Calculated ineither way, the results are impressiveand demonstrate in each case thatthe concordance rates among MZtwins exceed their correspondingrates among DZ twins. The fact thatthere is less than perfect concordancereveals that environmental factorsalso play a major role in the etiologyof schizophrenia.

Studies of MZ twin pairs reared

apart also point to the involvement ofgenetic factors in the etiology ofschizophrenia. Slater and Cowie(1971) compiled 17 such pairs, and 11of these (65 percent) were reported tobe concordant for schizophrenia.

The family and twin studies ofschizophrenia have a majormethodological flaw. Both types ofstudies cannot differentiate betweenthe influences of what is inheritedbiologically from what an individualacquires from the socioculrural andfamilial context in which he or she isreared. Thus, for such disorders asschizophrenia, genotype-envi-ronment correlations are likely to oc-cur, i.e., disordered environments(e.g., disordered inrrafamilialcommunication patterns) may occurconcurrently with a genetic predis-position for schizophrenia. In suchinstances, it is not possible to sepa-rate the effects of genetics from thoseof nongenetic influences, i.e., theenvironment. In recent years, inves-tigators have turned to adoptionstudies as the means of separatingthe respective influences of heredityand rearing environment.

Adoption Studies

The most compelling, if not convinc-ing, evidence that genetic factors areinvolved in the etiology of schizo-phrenia comes from a series of ele-gantly designed studies on adoptedchildren. The first such study wasthat of Heston (1966) carried out inOregon. This investigator studied agroup of 47 individuals bom to agroup of hospitalized schizophrenicmothers, separated from them atbirth and reared in foster homes. Acontrol group of 50 individuals wasselected from among children whosemothers had no psychiatric disorderbut, nevertheless, had placed them

VOL 6, NO. 3, 1980 407

Table 2. Concordance rates in recent twin studies of schizophrenia (%)1

StudiesLocationof study

NorwayDenmarkU.S.A.2

FinlandU.K.

n (pairs)

5521951722

MZ twins

Pairwlse

25-3824-4814-270-36

40-50

Pro band-wise

4556433558

n (pairs)

9041

1252033

DZ twins

Pairwlse

4-1010-194-55-149-10

Pro band-wise

1526

91312

Kringten (1968)Fischer, Harvald, and Hause (1969)Poineta l . (1969)Tienari (1971)Gottesman and Shields (1972)

'Data from Gottesman and Shields (1976).Only mate twins studied.

into the same foundling homes as theexperimental group. Heston inter-viewed most of the subjects andfound that none of the controls andfive of the experimental group wereschizophrenic. Also, he found a rela-tively lower mean Menninger MentalHealth-Sickness score and highermean rates of criminality, mentaldeficiency, neurosis, and sociopathyamong the experimental subjects ascompared to the controls.

A study with somewhat similardesign was carried out by Rosenthalet al. (1968, 1971) in Denmark.Names of about 5,500 individualswho had been given up for nonfami-lial adoption early in life were ob-tained from an Adoption Register ofthe greater Copenhagen area. Fromthe records it was possible to learnthe names and other identifying in-formation of the biological andadopting parents. In this way thenames of about 10,000 biological par-ents were obtained. A search wasthen made in a second register, thePsychiatric Register, for those par-ents who had been admitted to apsychiatric facility. A Danish psychi-atrist first reviewed each of the hos-pital records and prepared anabstract which was transmitted to theAmerican collaborators who inde-

pendently rated each record andmade their own diagnostic assess-ment. Where full diagnostic consen-sus was reached that a parent was inthe schizophrenic range, the childgiven up for adoption was selected asan index case. From the remainingadoptees, controls were selectedwhose biological parents had noknown psychiatric history. The con-trols were matched to the index casesfor age, sex, age at transfer to theadopting family, and the socio-economic status of the adopting par-ents. A total of 76 index and 67 con-trol adoptees were subsequentlyinterviewed by a psychiatrist whodid not know to which group a par-ticular subject belonged. Among theindex adoptees, 30 percent received adiagnosis of schizophrenia orschizophrenia spectrum disorder1 ascompared to 17.8 percent among thecontrols. The three cases with diag-noses of chronic or process schizo-phrenia were all index cases whereas

1 Besides chronic or process schizo-phrenia, diagnoses of latent or borderlineschizophrenia, acute schizophrenic reac-tions, uncertain schizophrenia, andschizoid and inadequate personality areincluded in the schizophrenia spectrum(Kery et aL 1968).

no such diagnosis was found amongthe controls.

The frequency of schizophreniaspectrum disorders among the con-trols is surprisingly high, leading to asearch to refine diagnostic meth-odology. When three blind in-dependent clinical judges attemptedto reach a consensus diagnosis foreach subject, 32 percent of the indexgroup and 25 percent of the controlsreceived a schizophrenia spectrumdiagnosis (Haier, Rosenthal, andWender 1978)! However, when aschizophrenia spectrum diagnosisrequired both a consensus diagnosisand a divergent profile on at leastone clinical scale of the MinnesotaMulta'phasic Personality Inventory(MMPI), 21.9 percent of the indexcases (including the three chronicschizophrenic cases) and 6.3 percentof the controls received spectrumdiagnoses (Haier, Rosenthal, andWender 1978). The possibility thatparents who give their children upfor adoption may include personswith a substantially higher rate ofpsychiatric disturbances than parentsin the general population may ac-count somewhat for the elevatedrates found among the controls(Horn et al. 1975).

In contrast to Heston's (1966)

408 SCHIZOPHRENIA BULLETIN

study, Rosenthal et al. (1968) foundno mental retardation, criminality, orsociopathy among the Danish indexadoptees. Several factors may ac-count for the differences between thetwo studies; these are discussed byShields, Heston, and Gottesman(1975). Despite the differences, bothstudies agree in their main finding,i.e., that the offspring of a schizo-phrenic parent have substantially thesame risk for the disorder whether ornot they are raised by that parent.This finding strongly suggests theoperation of genetic factors.

Further evidence comes fromanother study of the Danish adop-tees carried out by Kety et al. (1968,1975). From the Psychiatric Registerand other files the names were ob-tained of adoptees who had beenadmitted to a psychiatric facility; 33such index cases were found. Fromthe remaining adoptees a matchedcontrol group was selected—free ofpsychiatric history. The Psychiatric

Register was searched once again forthe names of the adopting andbiological relatives of the index andcontrol adoptees. The histories of therelatives found in this Register wereabstracted and, as in the previousstudy (Rosenthal et al. 1968), all pre-cautions were taken to minimize in-vestigator bias. The results areshown in table 3.

The data clearly show a concentra-tion of schizophrenia spectrum dis-orders among the biological relativesof the schizophrenic index cases. Thefrequency of these disorders amongthe biological relatives of the indexcases was significantly higher thanthat among the controls; among theadopting relatives there was no sig-nificant difference. If disordered rear-ing led to the development ofschizophrenia in children, then itmight have been expected that agreater frequency of schizophrenicdisorders would have been foundamong the adopting rather than the

Table 3. Schizophrenia spectrum disorders among the biological andadoptive relatives of Index and control adoptees1

Biological relativesParentsSibsHalf-sibs

Adoptive relativesParentsSibsHalf-sibs

Index adoptees

n

632

85

150

6383

74

Number Inschizophrenia

spectrum

319

13

200

2

Control adoptees

n

635

88

156

66170

83

Number Inschizophrenia

spectrum

210

3

030

31 Data from Kety et ai. (1968).

biological relatives of the index adop-tees. The concentration of psy-chopathology among the biologi-cal relatives strongly supports thegeneric hypothesis.

Kety et al. (1975) reported the re-sults of psychiatric interviews ofthese biological and adoptive rela-tives. In all, 345 relatives were eitherinterviewed or supplied adequate in-formation about themselves. The in-terviews were carried out by aDanish psychiatrist who did notknow to which group a particularrelative belonged. Edited transcriptsof the interviews were indepen-dently assessed by the American col-laborators who arrived at a consen-sus diagnosis. The results are shownin table 4.

These investigators confirmed thata significantly greater frequency ofschizophrenia spectrum disordersoccurred among the biological thanamong the adoptive relatives of theschizophrenic adoptees. In the initialreport (Kety et al. 1968), less than 5percent of the relatives received aschizophrenia spectrum diagnosis,whereas in the more recent reportnearly 20 percent of the relativeswere so diagnosed—a four-fold in-crease. This finding suggests thatconsiderably more psychopathologyoccurs in the population than reachesthe attention of psychiatric facilities.

Table 4 also shows data on the fre-quency of psychopathology amongthe relatives of a group of 23"screened" controls, all of whomwere interviewed and shown to befree of a schizophrenic disorder.Again, there was a significantlyhigher rate of schizophrenic spec-trum disorders among the biologicalrelatives of the index cases thanamong the relatives of the"screened" controls.

Among the biological relatives,Kety et al. (1975) found 63 paternal

VOL 6, NO. 3, 1980 409

Table 4. Frequency of schizophrenia spectrum disorders In the relatives of schizophrenic and controladoptees1

Biological relatives Adoptive relatives

Group

Index cases

All controls

Screened controls

n

173

174

113

NumberInterviewed

118

140

86

ri*

I*

Schizophreniaspectrum

37 (21.4%)

19 (10.9%)*\ 11 ( 6.4%)

n

74

91

64

NumberInterviewed

35 fNS

48J

Schizophreniaspectrum

4 (5.4%)

7 (7.7%)NS

34 3 (4.7%)

'Data from Kety et al. (1975)." p < a 0 1 ; NS, not significant

half-sibs of index cases and 64 of con-trols. In this group of half-sibs, therewere 16 individuals who received adiagnosis of schizophrenia spectrumdisorder; of these, 14 were amongthe relatives of the index cases andonly 2 were related to the controls.Since paternal half-sibs share a fatherrather than a mother in common, thefindings suggest the absence of ma-ternal effects, i.e., that prenatal andperinatal factors are not involved inthe etiology of schizophrenic disor-ders, at least in these relatives. Thedata again strongly implicate geneticfactors.

Wender, Rosenthal, and Kety(1968) studied the psychologicalcharacteristics of a group of biologicalparents who had raised their ownschizophrenic children, as comparedto a group of matched parents whohad adopted either a child who be-came schizophrenic or a normalchild. These investigators found thatthe adopting parents of schizo-phrenics were less disturbed than thebiological parents of such individu-als, suggesting that parentalpsychopathology was not a precon-dition for the development ofschizophrenia in the offspring.

Wender et al. (1974) examined the

role of parental psychopathology inthe production of schizophrenia inoffspring who were not known to begenetically predisposed to this disor-der. A group of 69 Danish adopteesborn to a schizophrenic parent butreared from an early age by unrelatedadopting parents (index group) and agroup of 69 matched control adop-tees whose parents had no recordedpsychiatric history were compared.toa group of 28 adoptees who, like thelatter group, had nonschizophrenicbiological parents, but unlike them,had an adoptive parent with aschizophrenia spectrum diagnosis.These latter subjects constituted thecross-fostered group. All subjectswere interviewed, and efforts weremade to maintain blind proceduresin order to determine an unbiasedrelative rating of psychopathologyfor each individual. These re-searchers found that the control andcross-fostered groups were not sig-nificantly different in their degree ofrated psychopathology. When testedagainst the mean score of the indexadoptees, those of the control and •cross-fostered subjects were signifi-cantly lower. These data suggest thatthe experience of being reared in aschizophrenic home does not in-

crease the risk for schizophrenia inindividuals unless a genetic predis-position for the disorder is alreadypresent.

Wender et al. (1974) also foundthat the mean psychopathology scoreof children of schizophrenic motherswas not significantly different fromthose of schizophrenic fathers andthat there were no greater psycho-pathogenic effects of the schizo-phrenic parent on the same-sexedchild.

Rosenthal et al. (1975) havesuggested that although genetic pre-disposition and the quality of rearingboth may affect the development ofpsychopathology, the amount of var-iance accounted for by rearing tendsto be low. These workers rated thedegree of psychopathology and thequality of the parent-child relation-ship in index, control, and cross-fostered adoptees and in a group ofnonadopted individuals, born to andreared in a home with a schizo-phrenic parent. The individuals inthis latter group and the index adop-tees (both groups with a biologicalschizophrenic parent) showed themost severe psychopathology. Theworst parent-child relationshipswere found in the cross-fostered and

410 SCHIZOPHRENIA BULLETIN

nonadoptee groups. Rosenthal et al.(1975) found that the cross-correlation between child psycho-pathology and quality of parent-childrelationship was higher for the twogroups without a schizophrenicbiological parent (i.e., the controland cross-fostered groups) than forthe index adoptees and nonadopteegroup. Thus the rearing environmentappeared to play a relatively greaterrole in producing normal or psy-chopathological behavior in indi-viduals without a genetic loading forschizophrenia than it did for indi-viduals with such loading.

Rosenthal et al. (1975) also foundthat there were no significant differ-ences between index and controladoptees with respect to the qualityof the (adoptive) parent-child rela-tionship. Nevertheless, index adop-tees scored higher than controls ontheir psychopathology scores,suggesting that the greaterpsychopathology of the formergroup was due to generic factorsrather than to disordered rearing.

Evidence of another sort is pre-sented by Wynne, Singer, andToohey (1976). Working blindly,Singer analyzed the Rorschach pro-tocols of the biological and adoptingparents of the Wender, Rosenthal,and Kery (1968) study and, with as-toundingly high accuracy, was ableto differentiate the biological andadopting parents of schizophrenicindividuals from the adopting par-ents of normal individuals. The samedegree of Rorschach psychopathol-ogy was shown by both the adoptingand biological parents of schizo-phrenics, and both groups were sig-nificantly different from the adoptingparents of normal subjects. In an at-tempt to replicate the study onanother sample, Wender et al. (1977)found that the biological mothers ofschizophrenics tended to show more

Rorschach psychopathology thaneither the adopting mothers ofschizophrenics or the biological par-ents of a group of nonadopted re-tarded children. Wender et al. (1977)suggest that test set might accountfor the differences between theWynne, Singer, and Toohey (1976)study and theirs. The adopting par-ents of schizophrenics were, in onecase, informed, before testing thatthey had been chosen because oftheir adopting status, whereas in themore recent study they were re-cruited on the basis of a consecutivesample of hospital admissions andtheir adopting status was purport-edly not highlighted. Wender et al.suggest that as a result of this latterstrategy, the adopting parents didnot show any greater test anxietythan the other parents and, undersuch conditions (of presumably con-stant anxiety for all groups), only themothers of schizophrenics showedsignificant Rorschach psychopathol-ogy. If these latest findings can bereplicated, it might suggest that dys-functional communication styleshave a genetic component, andshould not be treated as an environ-mental variable as has been done inthe past.

Kety et al. (1975) found that diag-noses of questionable schizophreniaand of schizoid or inadequate per-sonality were distributed equallyamong the biological relatives ofschizophrenic and nonschizophrenicadoptees, whereas the diagnoses ofchronic, latent or borderline, and un-certain schizophrenia tended to clus-ter together among the biological rel-atives of schizophrenic adoptees.Thus, the latter disorders appear toconstitute a group of genetically re-lated disorders, whereas the rela-tionship of the former ("soft-spectrum") disorders to the gene orgenes that produce schizophrenia is

less clear. Differences of opinionexist as to the inclusion of sociopathicbehaviors in the schizophrenia spec-trum. Data of Heston (1966) and ofBender (1975) suggest that theyshould be included. Data of Kety etal. (1975) suggest that they shouldnot.

Rosenthal and his co-workersbelieve that a relationship existsbetween the "soft-spectrum" diag-noses and schizophrenia. Prelimi-nary data (Rosenthal 1975) suggestthat "soft-spectrum" diagnosesoccur among a substantial fraction ofthe co-parents (i.e., the matingpartners of the biological index par-ent) of schizophrenic adoptees.When the coparent had a "soft spec-trum" diagnosis, it appeared to in-crease the risk for a schizophreniaspectrum diagnosis in the adoptee.When the former diagnosis was ab-sent in the co-parent, it was alsolikely to be absent in the adoptee.Rosenthal (1975) has suggested thatthe genetic input from a soft spec-trum co-parent adds to the geneticinput from a chronic schizophrenicparent to promote an increasedschizophrenic manifestation in theoffspring. Rosenthal's data alsostrongly suggest that substantial as-sortative mating occurs between in-dividuals who have a predispositionto schizophrenic disorders.

A full detailed report of all the find-ings of the Danish adoption studiesis not yet available, and it may beyears before we can assess the fullimplications of the Kety-Rosenthalwork. Like the family and twinstudies, the adoption studies are notwithout their sampling and othermethodological difficulties. Some ofthe replications are not always con-sistent with the main trends in thedata. For example, Wender et al.(1974) did not find a significant dif-ference between index and control

VOL 6, NO. 3, 1960 411

groups with respect to the rate ofdefinite or uncertain schizophrenia.These investigators accounted fortheir results by suggesting that therewas an inflated rate of psychopathol-ogy among the individuals in thecontrol group. Also, examination ofthe data of Kety et al. (1975) suggeststhat the rate of psychopathologyamong the biological half-sibs ofschizophrenic adoptees was 19.2percent, whereas among the biologi-cal parents of these adoptees, therate of schizophrenia (definite or un-certain) was 12.1 percent. Unfortu-nately, half-sibs only share one-quarter of their genes in commonwith their schizophrenic relatives,whereas biological parents shareone-half of their genes in commonwith their affected children. Geneticmodels cannot reasonably accountfor data in which the frequency of atrait is as high or higher among moreremotely related relatives thanamong closer ones. These apparentinadequacies may yet be accountedfor when the full report is in, and inno way do they weaken the majorthrust of the Danish adoptionstudies.

Individual studies—family, twin,adoption—all contain methodologi-cal problems and flaws, and can besubjected to greater or lesser criti-cism. Nevertheless, the overwhelm-ing direction of the findings of allthese studies, carried out in differentcountries and at different times, isremarkably consistent in confirmingthat genetic factors are involved inthe etiology of schizophrenia. Also,these studies confirm that althoughin many cases a genetic predisposi-tion to schizophrenia may be anecessary precondition, it is by nomeans a sufficient condition to pro-duce the disorder. Both genes andenvironment play a substantial rolein the etiology of schizophrenia.

A few words need to be said aboutthe mode of inheritance of the geneor genes involved in the etiology ofschizophrenia. Rosenthal (1977) hasrecently reviewed this topic.

It has been known for many dec-ades that schizophrenia is not trans-mitted in a simple Mendelian way.Of course, many traits in many dif-ferent species, including humans, donot show a Mendelian pattern of in-heritance, yet have important geneticdeterminants. For example, suchcommercial traits as animal size, eggproduction, milk yield, etc., have allbeen shown to have a complexnon-Mendelian, multifactorial ge-netic determination and have beenresponsive to artificial selection pro-cedures. Also, many importanthuman characteristics (e.g., IQ,height, etc.) show a pattern of inheri-tance which can best be understoodas being multifactorially determinedand which can be analyzed by quan-titative genetic methods. Some traitsand diseases seem to show a quasi-continuous distribution; that is, theymanifest all-or-none characteristicsand do not follow a Mendelian modeof inheritance.

Using a quantitative geneticapproach, a field to which he hadalready contributed, the geneticistFalconer (1965) advanced a model toaccount for such quasi-continuousdiseases as schizophrenia, pyloricstenosis, diabetes, cleft lip (±) cleftpalate, etc. The model presupposesthat underlying the etiology of a dis-order is a continuously distributedvariable, liability, that encompassesall the endogenous and exogenousfactors predisposing to the disorder.The distribution of the liability can beconceived as being represented by anormal, bell-shaped curve, at oneend of which is a point called thethreshold, which demarcates indi-viduals who are affected from those

who are not. The point at which thethreshold is placed on the curve canbe determined by the prevalence ofthe disorder in the general popula-tion. Given the prevalence ratesamong different classes of relatives ofaffected individuals, it is possible touse the model to calculate the herita-bility of the liability to the disorder.Gottesman and Shields (1966) werethe first to apply the Falconer modelto the inheritance of schizophreniaand calculated that the heritability ofthe liability to schizophrenia wasabout 85 percent. Simply put, herita-bility represents the proportion ofthe degree of resemblance betweenrelatives accounted for by geneticfactors.• The major problem with the

Falconer/Gottesman-Shields ap-proach was that it left many inves-tigators intellectually dissatisfied.The model introduced "new"concepts—liability, heritability—both of which had limiting defini-tions and generalizability and couldonly be understood in terms of popu-lations rather than of individualpedigrees. Furthermore, the modeldid not appear to be of much use toresearchers who were trying to un-derstand the biochemistry andneurophysiology of schizophrenia.These investigators were hoping fora more simple model, one more likethat of phenylketonuria (PKU) orother inborn errors of metabolismwhich appeared to have a morestraightforward pattern of inheri-tance associated with a specific chem-ical defect. Given the new impetussupplied by the results of the adop-tion studies, the problem of themode of inheritance of schizophreniawas subjected to renewed attack.

Using currently available familyand twin data and rather sophisti-cated computer programs, Kidd andCavalli-Sforza (1973) and Kidd (1975)

412 SCHIZOPHRENIA BULLETIN

found that the data were compatiblewith a single gene model which in-corporated a threshold concept.From their calculations it appearedthat the gene had a frequency ofabout 10 percent and a thresholdsuch that 50 percent or more of thehomozygotes would be affected.

Matthysse and Kidd (1976) ex-panded on this approach by inves-tigating the extreme genetic models,i.e., a single major locus ormonogenic model (SML) and themultifactorial or polygenic model(MF). These workers calculated esti-mates of the parameters of the twomodels including the gene fre-quency, the likelihood of pheno-copies, and the relative incidenceof schizophrenia in heterozygotesand homozygotes. Based on the ratesof schizophrenia in the general popu-lation and among sibs and childrenof schizophrenics (i.e., the caseswhich provide the largest body ofdata in the literature), it is possible todetermine the expected incidenceamong MZ twins and in dual mat-ings (children of two schizophrenicparents). The expected and observedrates are shown in table 5.

Matthysse and Kidd found thatneither of the models accountedadequately for the observed data.The SML model provided estimatesthat were too low and the MF model

provided estimates that were toohigh relative to the actually observedincidences among children of two af-fected parents and MZ twins.Nevertheless, the two models pro-vided some interesting perspectives.In the SML model, the genetic com-position of the affected populationvaried according to the frequency ofthe allele that promoted the de-velopment of the disorder. At rela-tively low frequencies of the allele,about 60 percent of schizophrenicswere estimated to be phenocopies,i.e., environmentally producedmimics of the genetically determinedform of the disorder. In other words,these affected individuals would begenetically "normal" persons, andthe disorder would develop becauseof environmental influences. Theremainder of the cases would bemostly heterozygotes. At relativelyhigh frequencies of the schizo-phrenia-promoting allele, thenumber of phenocopies drops andthe proportion of heterozygotes in-creases correspondingly. At all allelicfrequencies, the proportion ofschizophrenics who were homozy-gotes is low. Thus under some condi-tions of this model, genes play anextremely important role when theyare present in double dose, but suchindividuals would be rare, evenamong affected individuals.

Table 5. Observed and expected rates of schizophrenia1

Group

Dual matingsMZ twins

Observed (%)*

39.047.0

Expected

Single majorlocus model

19.919.9

rates (%)

Multifactorialmodel

54.061.0

1 Data from Matthysse and Kidd (1976).1 Data based on observed incidences of 0.87 percent In tie general population, and 8.7 and •\Z0 percentamong stn and chldren of probands, respectively.

Under the MF model, Matthysseand Kidd found that about 9.1 per-cent of schizophrenics had such ahigh generic risk that 99 times out of100 they would become schizo-phrenic virtually irrespective of envi-ronmental circumstances. Accordingto this model, in 1 of 11 schizo-phrenics, the disorder is almost to-tally genetically determined.

Both models predict genetic het-erogeneity among schizophrenics.Not every schizophrenic will havethe same genetic makeup with re-spect to the schizophrenia-promoting genes. This, of course,would pose serious difficulties forinvestigators who would like to ob-tain a relatively homogeneous groupof affected individuals for researchpurposes.

Kidd and Matthysse (1978) ad-dressed themselves to the future re-search strategies that may need to beadopted in the study of schizophre-nia, particularly in an attempt to re-solve the underlying heterogeneity.Kidd and Matthysse (1.978) suggestthat the screening of large samples ofunrelated individuals be done toidentify individuals with markedlydeviating values on biochemical andneurophysiological variables. Thesemay be followed by classical familystudies of such individuals. Other re-search possibilities include the studyof children of twins, separationstudies on groups such as half-sibs,adoptees, and MZ twins rearedapart. Perhaps the most useful kindsof studies are those involving nuclearfamilies and multigenerationalpedigrees, that is, large families en-compassing several generations andseveral sibships. Both Kidd andMatthysse (1978) and Rieder andGershon (1978) argue that thesegroups probably constitute the bestmaterial on which to test genetichypotheses linking various variables,

VOL 6, NO. 3, 1980 413

biological and psychological, toschizophrenia.

Genetic Counseling inSchizophrenia

Discussion of this topic may be foundin articles by Heston and Gottesman(1966), Kay (1978), Kety, Matthysse,and Kidd (1978), and Tsuang (1978).Several difficulties are encounteredin providing adequate genetic coun-seling to patients and their relatives.Available empiric risk figures are av-erages derived from a wide range ofindividual values from diverse popu-lations. An average figure may not beappropriate to the individual seekingcounseling. Also, as Kety, Matthy-sse, and Kidd (1978) point out, em-piric risk figures are derived fromand are only applicable to cases ofclassical chronic schizophrenia andnot to the other forms, such as latentor borderline schizophrenia andacute schizophrenia about which lessis known with respect to recurrencerisks. Furthermore, the mode ofinheritance of the gene or genesinvolved in the etiology of schizo-phrenia is not known. The modelscurrently available are too subtle andabstruse for most counselees to com-prehend; the models are likely to beperceived as intellectual exercises. Itis also important-to keep in mind thatrisk figures only have relevance forpopulations. Individuals tend to per-sonalize and dichotomize the riskfigures received in generic counsel-ing (Lippman-Hand and Fraser1979). Thus for groups of sibs of af-fected individuals, the average riskfor schizophrenia may be 1 in 10, butfor any given person and any givenpregnancy, the individual will eitherhave or not have an affected child.The generic counselor needs to havea good understanding of how indi-

viduals process ego-threatening in-formation under conditions of uncer-tainty Qanis and Mann 1977; Kessler197%; Pearn 1973; Tversky andKahneman 1974) to appreciate thispoint.

Schizophrenia has enormous im-pact on the family; parents of af-fected individuals have a profoundsense of failure, inadequacy, guilt,and shame. To imagine that one hastransmitted a gene or genes to one'soffspring that are responsible for thechild's illness often exacerbates thesefeelings and further erodes the par-ent's self-esteem. If parents have notblamed themselves for their child'sillness, it is not unusual that theyhave been blamed by other relativesand, not infrequently, by the profes-sionals with whom they have comein contact. It is no wonder then thatparents of affected individuals comefor genetic counseling relatively in-frequently (Reed 1972) and, whenthey do come, do so with high levelsof defensiveness.

Since many cases of schizophreniahave their onset in the postpubertalyears, many parents of schizo-phrenics have either completed oralmost completed their reproduction.Nevertheless, such individuals mayrequest genetic counseling, often onbehalf of their children, affected andunaffected. Concern for one's chil-dren may be used as a means of ob-taining personal help from a profes-sional. By focusing on the children,the parents may evade or avoid need-ing to deal with the interpersonaldifficulties which have been precipi-tated by the illness of the child. Insome cases, when the genetic coun-selor becomes complicit with theparents in focusing on the child atthe expense of not dealing with theparental dynamics, genetic counsel-ing may actually exacerbate familydysfunctions.

In my own experience, the genericcounseling of affected individualsgenerally takes one of two forms:Most often, genetic counseling is re-quested on behalf of the affected in-dividual and/or the person is referredto genetic counseling by a publichealth nurse, physician, or otherhealth professional because theprofessional is disquieted by thereproductive plans of the affectedindividual. In such cases, the profes-sional generally makes either anexplicit or implicit demand on thegenetic counselor to persuade the in-dividual not to have children. Suchreferrals are generally nonproduc-tive, as the counselee comes in al-ready suspicious, and the confidencethat needs to develop for effectivenondirective genetic counseling tooccur cannot be established.

Less frequently, the affected indi-vidual or the spouse requests thecounseling. If either or both coun-selees are in psychotherapy, consul-tation with the psychotherapistshould be sought, and the geneticcounseling should become an inte-grated part of the psychotherapeuticprocess. Such requests for counsel-ing often involve important ther-apeutic issues, and the managementand timing of the counseling mayhave important consequences for thetherapeutic outcome for the indi-vidual or family.

Affected individuals and/or theirspouses sometimes request geneticcounseling because of the psycho-tropic medications to which theymay have been subjected and theirconcerns about the effects of suchpharmacological agents on the genesthey carry and about the possibleconsequences for a healthy fetus.Unfortunately, this is another areaabout which hard facts are not avail-able.

The unaffected sibs of schizo-

414 SCHIZOPHRENIA BULLETIN

phrenics or prospective spousessometimes also request genetic coun-seling. The timing of requests forsuch counseling should be carefullyexplored by the counselor. The fearthat one is going mad or may alreadybe mad may motivate the quest forgenetic counseling, particularly ifprecipitated by some family crisis(which may or may not be related tothe affected individual). Not in-frequently, genetic counseling issought by one spouse as a means ofobtaining a professional ally or sup-port for his or her side in an interper-sonal conflict over reproduction. Thecounselor needs to explore carefullythe motivation for obtaining geneticcounseling at a particular time in thelife cycle of a family, to avoid exacer-bating already existing family dys-functions.

Children of a schizophrenic parentare another group that may seekgenetic counseling. Here, too, themotivations for requesting counsel-ing, the meaning of the risk figures,and the consequences of knowing ornot knowing that one is at risk forschizophrenia all need to beexplored.

Tsuang (1968) has described sevenbasic steps in the genetic counselingfor psychiatric disorders. These willbe listed with some additional com-mentary of my own. The steps in-clude:

1. Making an accurate diagnosis.Tsuang points out several caveats inthis area. The counselor needs to re-member that at the present state ofour knowledge it is not possible todifferentiate unequivocally betweencases of schizophrenia with highgenetic loading, phenocopies, folie adeux, etc., even within the samefamily.

2. Obtaining a family history. Notinfrequently the counselor may needto rely on medical records of doubtful

value and on secondhand informa-tion provided by relatives who areneither objective nor unbiased. In thediscussion of family history, familymyths may emerge about the af-fected individual and his or her rela-tionship with other family members.These myths may be based on mis-taken notions and may play a keyrole in maintaining dysfunctionalfamily dynamics. Although the cor-rection of mistaken notions may be aworthy goal in genetic counseling,achieving this goal may be difficult.Family members may resist newinput and reject ideas which runcounter to their own system of be-liefs. Alteration of these belief sys-tems may have important conse-quences for the family, not always ofa negative kind. However, the coun-selor may need to engage in longerterm work with the family if an at-tempt is made to alter the myths onwhich family functioning is based.Also, in discussing various relatives,strong feelings of anger, disap-pointment, bitterness, love, longing,etc., may emerge with which thecounselor may need to deal.

3. Estimation of the recurrencerisk. There is a plethora of modelsthat the genetic counselor may use inestimating a recurrence risk, includ-ing single gene, multifactorial, andmodels of genetic heterogeneity. Allmay be consistent with existing data.Most counselees would neither ap-preciate nor understand the complexmodels with which geneticists deal.In general, counselees come to anexpert like a genetic counselor forunequivocal certainties and, unfor-tunately, this is what we seldom canprovide at the present state of affairs.The fact that there are ambiguities inour understanding of the mode oftransmission of schizophrenia maytend, as ambiguities usually do, toincrease the counselees' already

existing anxieties, and not in-frequently erode their confidence inthe counselor.

4. Psychosocial evaluation of thecounselee. Perhaps this should bethe first step in the process of geneticcounseling, and should occur beforethe counselor becomes locked into aprocedural course which may turnout to be inappropriate in light of thecounselee's needs and motivations.

5. Dealing with the risk/burdenratio. The counselor attempts to helpthe counselees weigh the estimatedrecurrence risk against the burden ofthe disorder. Unfortunately, risk andburden are not orthogonal variables;counselees generally experience therisk as an integral part of the burdenof genetic disease (lippman-Handand Fraser 1979). Also, discussions ofrisk/burden ratios presuppose thathuman cognitive-emotionalmechanisms are geared toward suchdiscussions. Evidence suggests thatthey are not (Janis and Mann 1977).In the evaluation of risks and bur-dens, individuals take simplifyingsteps and shortcuts which may leadto end points unanticipated by thecounselor.

6. Formulating a plan of action.Tsuang (1978) suggests that thecounselor needs to play a relativelydirective role in this area. This pre-supposes that "doctor knows best"with respect to other peoples' repro-ductive plans and health decisions, asupposition which may not necessar-ily be the case.

7. Followup. The counselor needsto have a clear sense of his or herown motivation and goals in provid-ing followup. If, on followup, thecounselor discovers that the informa-tion provided during the course ofgenetic counseling has been dis-torted or misunderstood, whatcourse will be followed then? To at-tempt to reeducate and inform at that

VOL 6, NO. 3, 1980 415

point may be as futile as the first at-tempt, if the defensive, coping, orother conditions which led to the dis-tortion in the first place continue toprevail.

One needs to remember, in theprovision of genetic counseling inschizophrenia, that the disorder itselfinvolves, among other things, a dis-tortion of reality and an illogicalthinking and connection of ideas inwhich the entire family, affected andnonaffected, participates in manysubtle ways. The frequent distortionof genetic information found in ge-netic counseling (Shaw 1977) occurseven more so in the genetic counsel-ing of schizophrenia. All the issuesusually seen in genetic counseling(Kessler 1979a, 1979c) are present,often in an extreme or distortedform. Similarly, the feelings of fear,guilt, shame, confusion, etc., fre-quently manifested in genetic coun-seling may be present in an exacer-bated or distorted way. Requests forcounseling, the perception of the in-formation provided by the counselor,the interpretation of the recurrencerisk, and the perceived need to reachreproductive or health decisions fre-quently contain hidden agendas andare intertwined with a mishmash ofintrapsychic and interpersonal is-sues. Thus, the genetic counselorneeds to be trained and skilled indealing with these issues and needsto be willing to engage in more than abrief fact-finding and fact-giving ac-tivity (Kallmann 1956; Rainer 1975).Unfortunately, genetic counseling inthis area is sometimes done in a verycavalier way without taking into con-sideration the possible short- andlong-term consequences the counsel-ing might have for the individual andhis or her family. It is my strongbelief that genetic counseling inschizophrenia should only be givenby persons trained in the skills of

psychotherapy and, optimally,within the confines of thepsychotherapeutic encounter.

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The Author

Seymour Kessler, Ph.D., is affiliatedwith the Genetic Counseling Pro-gram, Health and Medical SciencesProgram, University of California,Berkeley, CA.