impact of genetic vulnerability and hypoxia on overall intelligence

Impact of Genetic Vulnerability and Hypoxiaon Overall Intelligence by Age 7 in Offspring

at High Risk for Schizophrenia ComparedWith Affective Psychoses

by Jill M. Qoldstein, Larry J. Seidman, Stephen L. Buka, Nicholas J. Horton,JoAnn L. DonateUi, Ronald O. Rieder, and Ming T. Tsuang

Abstract

Risk factors for schizophrenia, such as genetic vulner-ability and obstetric complications, have been associ-ated with cognitive deficits in schizophrenia. We testedthe association of these risk factors with general intel-lectual ability in offspring at high risk for psychosesand normal control subjects. Offspring of 182 parentswith DSM-IV schizophrenia or affective psychoseswere recruited and diagnosed from the Boston andProvidence cohorts of the National CollaborativePerinatal Project (NCPP). Control subjects from theNCPP were selected to be comparable with affectedparents based on the parent's age, ethnicity, study site,number of offspring enrolled in the NCPP, and pay-ment status, and on the offspring's age, sex, and his-tory of obstetric complications. Based on data prospec-tively acquired from pregnancy and events ofgestation, labor, delivery, and the neonatal period, wederived a measure of probable hypoxic-ischemicinsult. We also report on standardized measures ofgeneral intelligence (intelligence quotient [IQ]) col-lected at age 7. General linear mixed models were usedto test for the simultaneous effects of genetic vulnera-bility, defined as parental diagnosis, and probablehypoxic insult on age 7 IQ. Specificity of the effects forschizophrenia compared with affective psychoses andsex effects were also tested. Low IQ at age 7 was signif-icantly associated with genetic vulnerability to psy-choses, in particular with schizophrenia.

Keywords: Schizophrenia, high risk, genetics,obstetric complications, IQ.

Schizophrenia Bulletin, 26(2):323-334, 2000.

A large literature demonstrates that schizophrenia is a dis-order characterized by cognitive deficits. These deficitsinclude a reduction in overall intelligence and deficits inabstraction and other executive functions, attention, work-ing and declarative memory, psychomotor and motor

functions, and olfaction (Neuchterlein 1983; Goldbergand Weinberger 1988; Levin et al. 1989; Goldberg andSeidman 1991). Although the deficits have been wellcharacterized in many previous studies of schizophrenia,the relationship of these deficits to etiological risk factorsfen- schizophrenia is still not fully understood. Genetic andprenatal environmental risk factors for schizophrenia havebeen implicated in high-risk studies of offspring of par-ents with schizophrenia and case-control or cohort studiesusing birth cohorts examining prenatal and perinatalinsults. Some of these risk factors, such as family historyof psychosis, have been associated with cognitive deficitsin unaffected relatives, as well as in psychosis per se(Kremen et al. 1994).

Genetic risk factors have been implicated in the etiol-ogy of schizophrenia in numerous studies during this cen-tury (Faraone et al. 1985; Gottesman 1991). First-degreerelatives of schizophrenia patients have a seven to tentimes greater risk for schizophrenia than the general popu-lation (Gottesman 1991; Kendler and Diehl 1993; Tsuang1993); monozygotic twins exhibit approximately 50 per-cent concordance (Tsuang and Faraone 1995); and link-ages to a number of chromosomes have been demon-strated (e.g., Pulver et al. 1994; Schizophrenia LinkageCollaborative Group 1996; Faraone et al. 1998). Twinstudies also suggest that genetic vulnerability is not neces-sarily a sufficient cause but may interact with environ-mental risk factors, particularly those occurring in the pre-natal period. Prenatal and perinatal complications (PPCs)are more common in the histories of persons with schizo-phrenia (Parnas et al. 1982; McNeil and Kaij 1989; Bukaet al. 1993; Geddes and Lawrie 1995; McNeil 1995;Smith et al. 1995; Wright et al. 1995; Cannon 1996;Kunugi et al. 1996; Hultman et al. 1997; Jones et al.1998). Some studies have shown that subjects exposed toPPCs are up to twice as likely to develop schizophrenia

Send reprint requests to Prof. J.M. Goldstein, Massachusetts MentalHealth Center, 74 Fenwood Rd., Boston, MA 02115; e-mail: [email protected].

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Schizophrenia Bulletin, Vol. 26, No. 2, 2000 J.M. Goldstein et al.

(Geddes and Lawrie 1995). Previous birth cohort studieshave implicated conditions associated with hypoxia assome of the most likely risk factors for schizophrenia inadulthood (Cannon et al. 1989; McNeil 1991; Buka et al.1993; Dalman et al. 1999). Presumed hypoxia measureshave been demonstrated to have a number of otheradverse outcomes, including neurological and neurocog-nitive deficits in childhood, such as lower intellectualabilities (Naeye and Peters 1987; Seidman et al., thisissue).

General intelligence lower than average has beenobserved repeatedly in the premorbid histories of personswith schizophrenia (Aylward et al. 1984; Jones et al.1994; Kremen et al. 1998; Gilvarry et al. 2000). Further,high-risk studies of schizophrenia have identified a syn-drome of neuropsychological and social impairments inchildhood that are predictive of subsequent psychosis(Nuechterlein 1983; Cornblatt et al. 1989; Erlenmeyer-Kimling and Cornblatt 1992; Fish et al. 1992). Deficitshave been reported in concept formation, object sorting,and general intelligence, subsequently referred to as IQ(Mednick and Schulsinger 1968; Rieder et al. 1977;Nuechterlein 1983; Erlenmeyer-Kimling and Cornblatt1992). Neuromotor deficits (Orvaschel et al. 1979;Lifshitz et al. 1985; Asarnow and Goldstein 1986; Marcuset al. 1987), soft neurological signs (Auerbach et al. 1993;Buka et al. 1998), and attentional deficits (Rieder andNichols 1979; Cornblatt et al. 1989; Erlenmeyer-Kimlingand Cornblatt 1992) have been found consistently in off-spring at high risk for schizophrenia, all of which mayhave a negative impact on IQ performance. High-risk(Rieder et al. 1977; Mednick et al. 1978; Cornblatt et al.1989), birth cohort (Jones et al. 1994; Rantakallio et al.1997), and other case-control studies of schizophrenia(Aylward et al. 1984; O'Callaghan et al. 1992) have alsoshown that boys are more likely to experience premorbidIQ deficits than girls, suggesting that the male fetus maybe particularly vulnerable. Finally, there is some evidenceindicating that IQ deficits are not specific to schizophreniaand have been found, although milder than in schizophre-nia, in persons with affective psychoses and offspring athigh risk for affective psychoses (van Os et al. 1997;Tarrant and Jones 1999; Gilvarry et al., in press).

Ours is one of the few studies of schizophrenia toexamine both genetic vulnerability and prenatal environ-mental risk factors in one investigation. We are conduct-ing a 30-year longitudinal study of offspring at high riskfor psychoses, part of the New England LongitudinalStudies of Schizophrenia (Buka et al. 1999). We areprospectively investigating the independent and combinedimpacts of genetic predisposition to schizophrenia andPPCs on psychiatric, neuropsychological, and neurologi-cal status from birth through age 40. In the present study,

we investigated offspring at high risk for psychosis todetermine the impact of genetic vulnerability, defined byparental diagnoses of schizophrenia or affective psy-choses, and probable hypoxic insults, on cognition,defined as full-scale IQ at age 7. We hypothesized thatthere would be an effect of genetic vulnerability and pre-sumed hypoxic insults on IQ, particularly for male off-spring of parents with schizophrenia. We hypothesizedthat the interaction of genetic vulnerability with hypoxiawould be associated with lower IQ compared with effectsfor either exposure alone, particularly for offspring at highrisk for schizophrenia compared with affective psychoses.The findings from these analyses may help to identifyindividuals who may be at highest risk for psychosisthemselves, because IQ deficits have been found to beearly indicators of subsequent psychosis in adulthood(Jones et al. 1994; Kremen et al. 1998).

Methods

Sample Ascertainment The sample was originally ascer-tained between 1959 and 1966 from a community cohortof pregnancies drawn from the Providence and Bostonsites of the National Collaborative Perinatal Project(NCPP) of the National Institute of Neurological andCommunicative Disorders and Stroke (Niswander andGordon 1972). At these two sites, 17,741 pregnancieswere followed prospectively, and events of gestation,labor, delivery, and the neonatal period were systemati-cally assessed. Children's mental, motor, sensory, andphysical development was also assessed at 4 and 8months and 1, 4, and 7 years of age, including standard-ized measures of general intelligence at age 7.

Family history of psychiatric treatment was assessedat study intake and at the child's age 7 evaluation, whenmothers were asked about mental conditions that requiredhospital care or psychiatric treatment for themselves orfamily members. Approximately 3,200 parents respondedaffirmatively to these questions about prior psychiatrictreatment in their families. Out of a review of the 3,200records, 671 parents were identified with a history of psy-chiatric hospitalization (133 mothers in Providence and280 mothers in Boston; 78 fathers in Providence and 180fathers in Boston). Some of these cases had previouslybeen identified and studied by Rieder and colleagues(1977). An additional 115 parents with psychiatric hospi-talizations (74 mothers and 41 fathers) were identifiedthrough record linkages with the Massachusetts and RhodeIsland Departments of Mental Health. We obtainedapproval from institutional review boards for human stud-ies at several hospitals associated with the original studyand with the Massachusetts and Rhode Island Departments


Impact of Genetic Vulnerability and Hypoxia on Intelligence Schizophrenia Bulletin, Vol. 26, No. 2, 2000

of Mental Health and developed extensive procedures toprotect subject confidentiality.

The sample of 786 potentially affected parents con-sisted of 62 percent mothers and 38 percent fathers. Ofthe 786, 143 had been treated for conditions that werepresumably nonpsychotic (e.g., a single episode of majordepression or alcohol disorders). These subjects were notincluded in followup efforts. Of the remaining 643 par-ents, 503 (78.2%) have been located, 26 (4.0%) searchesare still in progress, and 114 (17.7%) were unlocatable. Ofthe located subjects, 48 (9%) refused participation, 366(73%) completed interviews, and 89 (18%) are at variousstages in the recruitment process. Subjects were locatedthrough a variety of methods, including through searchesof credit bureaus, address directories, death certificates,and motor vehicle reports, and by home visits. Our goalwas to ascertain 200 psychotic parents, half with schizo-phrenia and half with affective psychoses, and a compara-ble group of normal controls. We report here on the off-spring of 182 parents with DSM-FV psychoses (95 withschizophrenia and related psychotic spectrum disordersand 87 with affective psychoses; see below for diagnosticprocedures).

Normal control parents were selected to be compara-ble with parents with psychotic disorders based on theparent's age, ethnicity, study site, number of offspringenrolled in the NCPP, and payment status (public or pri-vate), and on the offspring's age, sex, and history ofPPCs. Eligible controls included all members of theNCPP who were not identified as potential index parentsand whose records indicated the absence of psychiatrictreatment We initially identified 268 normal control par-ents, based on the criteria listed above. Of these, 213(79%) were located, and to date 166 (78%) have beeninterviewed. Of the interviewed controls, 117 met our cri-teria for being "unaffected." Exclusion criteria were: AxisI psychotic disorder, bipolar disorder, or recurrent majordepression without psychosis; Axis II, Cluster A personal-ity disorders, history of psychiatric hospitalization; and/orfirst degree relative with a history of psychosis, mania, orsuicide.

Diagnostic Procedures. All subjects who were locatedand agreed to participate received the first of a two-partinterview. It has been previously argued that two-stagestrategies for case identification in the community resultin greater validity of diagnostic classification(Dohrenwend and Shrout 1981; Shrout and Fleiss 1981).The first interview assessed sociodemographic character-istics, medical history, developmental history (e.g.,schooling, educational or learning problems, headinjuries), and screening for psychiatric symptomatology.Psychiatric symptomatology was assessed using the

Quick Diagnostic Interview Schedule (Robins et al. 1989)to screen for Axis I disorders, and the self-reportPersonality Dimensions Questionnaire (Hyler 1990) toscreen for Cluster A, Axis II personality disorders (i.e.,schizotypal, schizoid, and paranoid personality disorders).Participants were also asked to sign releases for medicalrecords for psychiatric hospitalizations and outpatienttreatment. The first interview was conducted by systemat-ically trained B.A.-level research assistants. Three expertdiagnosticians (including J.M.G. and LJ.S.) reviewed theinformation to determine whether there was sufficient evi-dence to indicate potential psychosis and thus to warrant asecond interview to assess diagnosis, using the StructuredClinical Interview for Diagnosis (DSM-JV) (SCTD; Firstet al. 1996).

The second interviews involved formal clinicalassessments by M.A.- or Ph.D.-level interviewers whohad extensive experience using the SCID. Assessmentsincluded Axis I diagnosis of any form of psychotic, majoraffective, and bipolar disorders; and substance abuse ordependence (alcohol and drug). Time lines of the symp-toms and episodes were made to aid in dating the occur-rence of psychosis and affective syndromes. Family his-tory of psychiatric disorders was evaluated using theFamily Interview for Genetic Studies (Maxwell 1996).The expert diagnosticians reviewed all of the informationcollected, including medical records, if available, to deter-mine final best estimate diagnoses. Interview and medicalrecord data for 13 cases were reviewed by the three diag-nosticians for evaluation of reliability of lifetime diag-noses. There was agreement on all but one of the cases,whom two diagnosticians diagnosed as having schizoaf-fective disorder, depressed type, and one diagnosed ashaving major depression with psychosis. For the final"best estimate" parent diagnoses, two diagnosticiansmade a consensus diagnosis when there was any questionabout the diagnosis.

The 182 parents with DSM-IV psychotic disordersconsisted of 82 with schizophrenia; 16 with schizoaffec-tive disorder (8 with depressed type; 8 with manic type);81 with affective psychosis, including bipolar disorder (n= 36) or major depressive disorder with psychosis (n =45); and 3 with psychosis not otherwise specified. Basedon past literature on genetic transmission of schizophreniaand affective psychoses (Faraone and Tsuang 1985;Kendler et al. 1985; Gottesman 1991; Tsuang 1993), wecombined parents with schizophrenia, schizoaffective dis-order of depressed type, and psychosis not otherwisespecified into one group (i.e., schizophrenia and the psy-chotic spectrum disorders) and combined schizoaffectivedisorder of manic type with the bipolar disorders in a sec-ond group (i.e., affective psychoses). We conductedanalyses of offspring of parents with schizophrenia alone,



and the results were not substantially different. In addi-tion, IQ results in offspring of parents with major depres-sive disorder or bipolar disorders with psychosis weresimilar.

Obstetric Factor of Interest: Probable Hypoxic-Ischemic Complication. We hypothesized that indexesof abnormal fetal and neonatal development that havebeen associated with hypoxic-ischemic injury in theneonate constitute a class of complications of potentialsignificance for the development of schizophrenia. Weclassified participants as demonstrating probable hypoxic-ischemic complication (HI-P) according to signs of abnor-mal fetal and neonatal development obtained during aneonatal neurological examination and/or based on thepresence of a pattern of conditions suggesting compro-mise to intrauterine growth and development. Participantswere coded as evidencing HI-P if they were born at 37weeks or more of gestation and met at least one of the fol-lowing four criteria (divided into two groups):

A. Patterns of disordered growth and development dur-ing a pregnancy with complications:1. Small for gestational age (SGA), with preeclamp-

sia, meconium staining of the amniotic fluid, oruterine bleeding.

2. Postterm birth with preeclampsia.B. Neonatal neurological abnormalities in full-term baby

without seizures:3. Hyperactivity (suspected or definite).4. Hypotonia (suspected or definite).

The following operational definitions were used tomake this classification: (1) SGA—lowest 10th percentile ofbirth weight for each week of gestational age; (2) posttermbirth—42 or more weeks of gestational age; (3) preeclamp-sia—clinical rating of mild to severe preeclampsia, based onblood pressure readings, proteinuria, and edema; (4) meco-nium staining and uterine bleeding (during any trimester)—clinical rating based on obstetrician report; and (5) hyperac-tivity and hypotonia—clinical rating based on pediatricneurological examination at birth. This classificationapproach is a minor modification of recent work by ourgroup (Zornberg et al. 2000) and is used in a companionarticle (Seidman et al., this issue).

General Intelligence at Age 7. At age 7, an abbreviatedversion of the Wechsler Intelligence Scale for Children(WISC; Wechsler 1949), an age-standardized generalintelligence test, was administered. The subtests of theWISC consisted of information, vocabulary, digit span,comprehension, block design, picture arrangement, andcoding. The offspring sample included 405 subjects, ofwhom 87 percent (n = 353) had full-scale IQ at age 7.

There were no significant differences by high-risk statusas a predictor of missing data at age 7. Offspring of par-ents with psychoses were somewhat more likely to havemissing IQ data than normal control offspring, althoughthe difference was not significant

Data Analyses. First, we were interested in whether theimpact of HI-P would be associated with lower IQ in thegeneral population, as represented by the entire Boston andProvidence cohorts (n = 11,645). Recent studies have sug-gested that the effect of measures of hypoxia may differ inthe general population compared with a high-risk sample(DeLisi et al. 1988; Sacker et al. 1996). Thus, it is importantto understand the associations of HI-P in the general popula-tion in order to interpret findings in schizophrenia. To testour hypotheses, we used the general linear mixed model(Cnaan et al. 1997) to adjust for the correlation of observa-tions from siblings within a family. We specified a com-pound symmetry (exchangeable) covariance structure inSAS PROC MIXED (SAS Institute 1997), assuming thatmeasurements on any two siblings within a family have thesame covariance (i.e., are interchangeable).

We then tested for the impact of HI-P and geneticvulnerability, defined by the presence of parental psy-chosis, on full-scale IQ at age 7. We compared the high-risk offspring with their comparable controls rather thanthe general population cohort, because the comparablecontrols were free of other psychopathology that mightattenuate results.

We tested for the effect of genetic vulnerability forpsychosis and the specificity for schizophrenia comparedwith affective psychoses, controlled for potential con-founders such as mother's age at birth, socioeconomic sta-tus (SES), ethnicity, and study site. Two- and three-wayinteractions were tested for genetic vulnerability, HI-P,and sex of the offspring. There were no significant higherorder interactions between these factors. However, we hadlittle statistical power to test for three-way interactions.The association between sex and HI-P within parentalpsychosis groups was tested using generalized estimatingequation (GEE) regression models (Liang and Zeger1986), as programmed in SAS PROC GENMOD, whichallows for adjustment of intrafamilial correlation.

Results

In order to test the impact of HI-P in the general popula-tion, we combined the Providence and Boston NCPPcohorts (n = 11,645 for these analyses). Results from ageneral linear mixed model predicting age 7 IQ showedthat the effect of HI-P was significantly associated withlowered age 7 IQ by, on average, 2.75 points (beta =


Impact of Genetic Vulnerability and Hypoxia on Intelligence Schizophrenia Bulletin, Vol. 26, No. 2,2000

-2.75 (standard error = 0.39); t = -7.02 ( # = 2823), p <0.0001). The regression model controlled for potentialconfounders, including mother's age at birth, ethnicity,SES, study site, and sex of offspring, their pairwise inter-actions, and intrafamilial correlation among siblings.There were no significant interactions with sex of the off-spring on overall IQ at age 7.

We then tested for the impact of HI-P in the contextof genetically vulnerable individuals using our high-risksample compared with their normal comparison group.The sample consisted of 182 parents with diagnoses ofDSM-FV psychotic disorders, 117 comparable normalcontrols, and 405 of their offspring.

Table 1 presents demographic and other characteris-tics of the offspring sample by diagnostic group. Therewere 115 offspring of parents with schizophrenia, subse-quently referred to as "HR-SZ" (high risk for schizophre-nia), 127 offspring of parents with affective psychoses(HR-AFF), and 163 offspring of normal control parents(LR, for low risk). Tests of group differences showed nosignificant differences in sociodemographic characteris-tics by parental diagnostic status. All three groups had asimilar percentage of offspring who experienced HI-P,because we selected our control group to have comparablerates of overall obstetric complications in order to test forinteractions with genetic vulnerability. (Future analyseswill test whether HI-P rates in high-risk offspring are dif-ferent from those in the general population.)

Table 2 presents average full-scale IQ at age 7 inmale and female offspring by high-risk status and HI-P.Table 3 presents results from the general linear mixedmodel testing foT the association among high-risk status,

Table 1. Characteristics of the offspring sample1

HI-P, and age 7 IQ. Results from tables 2 and 3 showedthat there was a significant main effect of parental diagno-sis on age 7 IQ. Offspring at high risk for psychosis hadsignificantly lower IQs by age 7 than offspring at low risk.This was significant for the HR-SZ offspring and attenu-ated for the HR-AFF offspring (p = 0.17). The associationbetween parental psychosis and lowered age 7 IQremained after controlling for potential confounders (i.e.,SES, ethnicity, site, and mother's age at birth). Offspringwith HI-P did not have a significantly lower IQ at age 7than those without HI-P, after controlling for potentialconfounders (table 3). However, as table 2 shows, age 7IQ was lower in HR-SZ offspring with HI-P than without,even though the difference was not significant (p = 0.16).

Using a GEE regression model predicting the proba-bility of HI-P in high-risk males versus females, we foundsignificantly higher rates of HI-P in HR-SZ female off-spring compared with males (25% [14 out of 56] versus11.3% [7 out of 62], z = 2.54, p = 0.01); table 2 shows thedistributions). In contrast, there were comparable risks forHI-P in LR male offspring compared with females (12.4%[11 out of 89] versus 10.5% [8 out of 76]) and HR-AFFmales compared with females (13.3% [8 out of 60] versus10.6% [7 out of 66]) (tests were not significant).

Discussion

Findings in this study are consistent with other high-riskstudies (Rieder et al. 1977; Mednick et al. 1978;Erlenmeyer-Kimling and Cornblatt 1992) showing thatoffspring at high risk for schizophrenia have a significantlylower overall IQ in childhood than norrhal control off-

Characteristic

Male,%

Ethnicity, % Caucasian2

Family SES, mean (SD)

Boston site, %

III mothers, %

Mother's age at birth

%<20

% 20-34

% * 3 5

Probable hypoxic insult, %

Schizophrenia(n = 115)

54

90

5.37 (2.0)

67

70

13

73

14

15.7

Affective psychoses(n=127)

49

93

5.48(1.9)

71

77

7

83

10

11.8

Normal controls(n = 163)

55

93

5.68 (2.0)

73

—

4

82

14

12.3

Note.—SD « standard deviation; SES = sodoeconomic status.1 No significant differences across groups based on tor F tests.2 The other ethnic group was African-American.


to 00

Tab

le 2

. F

ull-s

cale

IQ

at

ag

e 7

fo

r o

ffsp

rin

g a

t h

igh

ris

k f

or

psych

oses c

om

pa

red

wit

h n

orm

al

co

ntr

ols

by p

rob

ab

le h

yp

ox

lc-

Isch

em

lc c

om

pli

ca

tio

ns

No

rmal C

on

tro

ls

Su

bje

cts

S

ub

jec

ts

IQ,

tes

ted

, n

3

foll

ow

ed

, n

4 m

ea

n (

SD

)

Off

sp

rin

g H

R-S

Z1

Off

sp

rin

g H

R-A

FF

2

Su

bje

cts

tes

ted

, n3

Su

bje

cts

foll

ow

ed

, n4

IQ,

mean (

SD

)S

ub

jec

ts

Su

bje

cts

IQ

,te

ste

d,

n3

foll

ow

ed

, n

4

mean (

SD

)

With

out

Hl-P

Male

Fem

ale

Both

Hl-P M

ale

Fem

ale

Both

67

67

134

11 8 19

78

68

146

11 8 19

104.6

(14.8

)

105.2

(11.2

)

104.9

(13.2

)

103.7

(11.4

)

97.8

(16.6

)

101.2

(13.8

)

45

39

84 2 14

16

55

42

97 7 14 21

10

1.5

(14

.9)

97

.5(1

8.0

)

99

.8(1

6.3

)

97

.5(1

0.6

)

95

.9(1

3.8

)

96.1

(13.1

)

50

47

97 8 7 15

52

59

111

8 7 15

10

0.9

(11

.5)

10

1.9

(14

.4)

10

1.4

(12

.9)

10

2.9

(5.6

)

97

.6(1

3.5

)

10

0.4

(10

.1)

Not

e.—

Hl-P

- p

roba

ble

hypo

xic-

isch

emic

com

plic

atJo

ns; H

R-A

FF =

hig

h ris

k fo

r affe

ctiv

e ps

ycho

sis;

HR

-SZ

.da

rd d

evia

tion.

1 Offs

prin

g in

this

cat

egor

y ha

d pa

rent

s w

ith s

chiz

ophr

enia

.2 O

ffspr

ing

in th

is c

ateg

ory

had

pare

nts

with

affe

ctiv

e ps

ycho

sis.

3 Den

otes

sub

ject

s te

sted

for

IQ a

t age

7.

4 Den

otes

sub

ject

s w

ho b

eton

g In

the

grou

ping

we

follo

wed

in

adu

lthoo

d.

high

ris

k fo

r sch

izop

hren

ia;

IQ -

int

ellig

ence

quo

tient

; SD

= s

tan-

to 3 z p 2

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Table 3. Main effects of genetic vulnerability and probable hypoxlc insult on age 7IQ1

Without Potential Confounders With Potential Confounders2

beta SE t df beta SE f df

Schizophrenia vs. normal controls

Affective psychosis vs. normal controls

Probable hypoxic insult

-5.20 1.99 - 2 . 6 1 " 261

-2.68 1.94 -1.39 261

-1.89 2.06 -0.92 88

-4.13 1.85 -2.25* 251

-2.54 2.03 -1.40 251

0.59 2.04 0.22 83

Note.—SE - standard error.1 Results are from a general linear mixed model.2 Analyses were controlled for main effects of mother's age at birth, ethnicity, sodoeconomic status, site, and sex of offspring.*p < 0.05; "p < 0.01

spring. Overall IQ reflects a general cognitive status that isaffected not only by individual biology but by the capacityfor negotiating school and social demands, domainsknown to be affected in schizophrenia. Results are alsoconsistent with studies demonstrating lower IQ in siblingsof patients with schizophrenia than in normal control sib-lings (Alyward et al. 1984). The validity of our findings isunderscored because we replicated the previous high-riskstudy, which used a subsample of the Boston NCPP cohort(Rieder et al. 1975, 1977; Rieder and Nichols 1979). Ourstudy is different from Rieder's early study because weexpanded the ascertainment strategy, added the Providencecohort, used personal clinical interviews, and updateddiagnoses based on current criteria.

In addition, consistent with recent birth cohort stud-ies, including the NCPP (Naeye and Peters 1987), proba-ble hypoxic insults were associated with significantlylower IQ by age 7 in the entire cohort, a general popula-tion sample. The effect was not significant in the high-risksample. The differences in the impact of hypoxia in thegeneral population compared with the high-risk samplecould be attributed to a lack of statistical power. That is,age 7 IQ was lower in high-risk offspring with HI-P thanin those without, although the difference was not signifi-cant However, it is also possible that hypoxic insults mayact differently in high-risk offspring and in the normalpopulation, a hypothesis we are currently testing. Thiswill contribute to understanding the issue, raised bySacker and colleagues (1996) and others (DeLisi et al.1988), that births to parents with psychoses may them-selves result in a higher probability of hypoxic insult.Thus, our measure of genetic vulnerability may havepotentially included hypoxic consequences. The previoushigh-risk study by Rieder and colleagues (1977) foundunexpectedly that IQ and SES had a lower correlation inthe high-risk sample than in the entire Boston cohort.These findings also suggested that factors associated withschizophrenia may act differently in high-risk samplesand in the general population.

Our analyses presented here have extended findingsfrom previous studies to show that the effect of parentaldiagnosis on overall IQ at age 7 is, in part, independent ofthe effect of probable hypoxic insult. Further, although theeffect is present in offspring of both diagnostic groups, itis stronger for offspring at high risk for schizophreniathan for offspring at high risk for affective psychoses. Anumber of other birth cohort studies (reviewed in Tarrantand Jones 1999) demonstrated adverse obstetric events inoffspring of affective psychotic parents (Dalman et al.1999) and adults diagnosed with affective psychoses (vanOs et al. 1997; Hultman et al. 1999). However, the natureof the obstetric events may have differed somewhat forthe two diagnostic groups (Hultman et al. 1999; Tarrantand Jones 1999). Further, a recent study of premorbidreading ability, a good indicator of premorbid IQ, foundthat relatives of patients with affective psychoses experi-enced a drop in IQ during childhood, although their base-line reading ability was higher than the normal controlsample (Gilvarry et al. 2000). Thus, the study suggestedthat patients with affective psychoses may experience alowered IQ, but it may "fall" to normal levels.

We did not find a significant effect of sex of the high-risk offspring on overall age 7 IQ. Further, we did not findhigher rates of presumed hypoxic insults in male HR-SZoffspring, as did previous high-risk studies. In fact, wefound significantly higher rates of hypoxic insults to HR-SZ female offspring than to male offspring. The unexpectedsex effect for female HR-SZ offspring can be explained bythree possibilities. First, methodological artifacts couldexplain the excess of HR-SZ females exposed to hypoxia.For reasons of confidentiality, we did not include study par-ents whose offspring were adopted at birth and not fol-lowed in the NCPP, and there may have been differentialadoption of male or female children by mothers with schiz-ophrenia. Second, differential nonparticipation of parentswith schizophrenia may have occurred depending on thesex of the child. The third and most likely explanation isthat there was differential mortality of male fetuses that



were genetically vulnerable and experienced hypoxicinsult. Previous studies of schizophrenia, including theNCPP Boston cohort (Rieder et al. 1975), reported morefetal deaths, especially for male fetuses, among motherswith schizophrenia than among mothers in the general pop-ulation. Thus, there would be fewer surviving males whowould be genetically vulnerable and exposed to additionalhypoxic events, and a higher percentage of surviving high-risk females with probable hypoxic insults. Although thisargument is a post hoc explanation of our findings, it raisessome interesting hypotheses to pursue with a larger sampleof high-risk offspring with and without presumed hypoxia.

There are three potential limitations to the study pre-sented here: dropouts from the study from birth throughage 7; unreliability of measures, such as age 7 IQ orpotential confounders, such as SES or maternal IQ; andsmall sample size for testing the interaction of presumedhypoxic insults and parental diagnosis. First, an examina-tion of the subjects in the entire cohort with missing dataat age 7 showed that mothers with schizophrenia wereless likely than the general population to bring their chil-dren for assessments at age 7. This, however, would atten-uate our results, because offspring at high risk for schizo-phrenia had lower IQs at age 7 than normal controls.

A second limitation is unreliability of the measure-ment of IQ at age 7 or potential confounders, such as SESor maternal IQ. Unreliability of the offspring's age 7 IQmeasurement could attenuate a potential effect of hypoxiaor parental status at age 7. We are currently examiningother cognitive domains at age 7 to further our under-standing of this. Unreliability of potential confounders ofthe relationship between IQ and presumed hypoxicinsults, such as SES or maternal IQ, could result in attenu-ation of the control of these potential confounders. Smalleffects on IQ are vulnerable to differences in SES.

Third, although our findings suggest the presence ofan interaction effect of genetic vulnerability and presumedhypoxic insult, it was not significant. However, we had asmall sample size that experienced both risk factors, andthus low statistical power to test for interaction effects.

It is important to keep in mind that the results pre-sented here were for overall IQ by age 7. Lack of a signif-icant finding at age 7 does not preclude the possibility thatsignificant associations would be present at older ages asbrain maturation continues. We know that after pubertythere are many changes in brain structure and function(Giedd et al. 1997) that may likely be affected by geneticvulnerability, exposure to hypoxic events, or both. Inaddition, as suggested by Seidman and colleagues (thisissue) and earlier by Rieder and colleagues (1977), weunderstand that, compared with age 7 overall IQ, theremay be larger differences in specific domains of cogni-tion, such as perceptual-motor skills and verbal IQ,

related to hypoxic events, genetic vulnerability, or both.Further, the developmental trajectory of domains of out-come may be a better predictor of adult outcomes than across-sectional examination at age 7 presented here(Goldstein et al. 1998; Kremen et al. 1998). Finally, it ispossible that alternative definitions of presumed hypoxiccomplications would yield different results. As discussedelsewhere (Seidman et al., this issue), there are noabsolute standards for defining hypoxic insults fromobstetric data collected 30 to 40 years ago. The currentstrategy is part of a work in progress.

The strengths of this study include our method ofascertainment and the fact that we have prospectively col-lected prenatal and postnatal events. We systematicallyidentified and diagnosed a parent sample of cases with psy-choses from a general population cohort, whose pregnan-cies were followed prospectively, and whose offspring wereevaluated from birth through age 7. Further, we are cur-rently evaluating these offspring in adulthood (now ages 35to 40). Thus, we can use premorbid information on the off-spring to predict who will experience psychoses them-selves, subsyndromal phenomenology of the illnesses, orcognitive deficits associated with psychoses, but withoutfrank illness per se. The birth cohorts, such as the NCPP,allow for the possibility of examining changes in develop-ment over time (Susser 1999) associated with geneticabnormalities and obstetric events. This approach may pro-duce a more realistic picture of how psychosis unfolds dur-ing development and the exact nature of specificity, if pres-ent, for schizophrenia compared with affective psychoses.

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Acknowledgments

This study was supported by National Institute of MentalHealth grant MH 50647 (M.T.T., principal investigator).The authors would like to thank Caitlin Thomas for helpin preparation of the manuscript.

The Authors

Jill M. Goldstein, Ph.D., is Associate Professor ofPsychiatry, Harvard Medical School, Department ofPsychiatry at Massachusetts Mental Health Center(MMHC), Boston, MA. Larry J. Seidman, Ph.D., isAssociate Professor of Psychology, Harvard MedicalSchool, Department of Psychiatry, MMHC, and Directorof Neuropsychology, MMHC. Stephen L. Buka, Sc.D., isAssociate Professor, Department of Maternal and Child



Health, and Nicholas J. Horton, Sc.D., is PostdoctoralFellow, Department of Biostatistics, Harvard School ofPublic Health, Boston, MA. JoAnn L. Donatelli, M.A., isResearch Associate, Harvard Medical School, Departmentof Psychiatry, MMHC. Ronald O. Rieder, M.D., isProfessor of Clinical Psychiatry, Department ofPsychiatry, College of Physicians and Surgeons,Columbia University, and Vice Chairman for Education,

New York State Psychiatric Institute, New York, NY.Ming T. Tsuang, M.D., Ph.D., D.Sc, is Stanley CobbProfessor of Pyschiatry, Department of Psychiatry,Harvard Medical School, MMHC; Director, HarvardInstitute of Psychiatric Epidemiology and Genetics,Boston, MA; and Professor, Department of Epidemiology,Harvard School of Public Health.


impact of genetic vulnerability and hypoxia on overall intelligence

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