Familial Association Between Allergic Disordersand Depression in Adult Finnish Twins

Marianne Z. Wamboldt,1,2* John K. Hewitt,3 Stephanie Schmitz,2,3 Frederick S. Wamboldt,1,2

Maija Rasanen,7 Markku Koskenvuo,6 Kalle Romanov,4,5 Jyrki Varjonen,4 and Jaakko Kaprio4,8

1National Jewish Medical and Research Center, Denver, Colorado2Department of Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado3Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado4Department of Public Health, University of Helsinki, Helsinki, Finland5Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland6Department of Public Health, University of Turku, Turku, Finland7Department of Medicine, Division of Pulmonary Medicine, University of Helsinki, Helsinki, Finland8Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland

Clinical studies have shown a relationshipbetween allergic disorders and depression,panic disorder, attention deficit/hyperactiv-ity disorder, and social anxiety for a signifi-cant subset of patients with these disorders.The nature of the relationship, whether dueto shared environmental or biologic vulner-abilities or as a result of the stress of chron-ic illness, has been less clear. By examiningthe covariance of atopic disorders and de-pressive symptoms in a community sampleof monozygotic (MZ) and dizygotic (DZ)twins, the contribution of genetic and/orshared environmental etiological factorscan be established. A Finnish sample of 1337MZ and 2506 DZ twin pairs, ages 33–60 years,was sent questionnaires inquiring abouthistory of asthma, eczema, and atopic rhini-tis, as well as the Beck Depression Inven-tory (BDI). The nature of the covariation be-tween twins of these symptoms wasinvestigated by fitting competing geneticand environmental models. Within-personcorrelation between atopic symptoms andBDI was 0.103 (P < 0.001) for the totalsample. Using the Mx statistical modelingprogram to fit the data to competing quan-titative genetic models, the best fittingmodel estimated that 64% of the association

between atopy and BDI was due to sharedfamilial vulnerability, primarily additivegenetic influences. Although the measuresfor allergic disorders and depression arecrude, this study supports the hypothesisthat there is a small shared genetic risk foratopic and depressive symptoms, and if rep-licated, may open research for commonmechanisms between allergic and depres-sive disorders. Am. J. Med. Genet. (Neuro-psychiatr. Genet.) 96:146–153, 2000.© 2000 Wiley-Liss, Inc.

KEY WORDS: genetics; atopy; depression;twin study; epidemiology

INTRODUCTIONAtopy is the tendency to develop a certain type of

allergy, which produces an immunoglobulin class E(IgE) antibody. IgE antibodies can sensitize the skin,leaving a characteristic erythema and wheal reaction,or other tissues, such as the intestines or bronchi. Thetendency to develop this type of allergy is inherited,although the allergy itself is not inherited. Diseasesexhibiting an IgE-mediated type of allergy includeasthma, allergic rhinitis (hay fever), urticaria (hives),and atopic dermatitis (eczema). These diseases tend tocluster in certain families, and they have significantheritability [Duffy et al., 1990; Edfors-Lubs, 1971; Har-ris et al., 1997; Jenkins et al., 1997; Laitinen et al.,1998; Lichtenstein and Svartengren, 1997; Nieminenet al., 1991]. There appear to be at least two genesinvolved in determining IgE responsiveness: a majorhistocompatibility complex (MHC)-linked control ofspecific immune responses and a non-MHC linked con-trol of the overall production of IgE [Hanson et al.,1991; Hopp et al., 1984; Ruffilli and Bonini, 1997].

A number of studies have linked atopic symptomsand/or disorders with a variety of psychological symp-

Data presented in part at the 9th International Congress onTwin Studies, Helsinki, Finland, June 4–6, 1998.

Contract grant sponsor: NIH; Contract grant numbers: RO1HL53391, K8MH01486, RO1 HL45157, M01-RR00051, MH15442, HD 07289, HD18426; Contract grant sponsor: Academy ofFinland; Contract grant numbers: 38332, 42044.

*Correspondence to: Marianne Wamboldt, National Jewish,1400 Jackson St., Room K701, Denver, CO 80206.

Received 9 March 1999; Accepted 5 October 1999

American Journal of Medical Genetics (Neuropsychiatric Genetics) 96:146–153 (2000)

© 2000 Wiley-Liss, Inc.

toms [Marshall, 1993]. Higher than normal rates ofIgE-mediated allergies have been reported in adultswith depression [Bell et al., 1991; Kennedy et al.,1996;Nasr et al., 1981; Ossofsky, 1976; Sugerman et al.,1982], panic disorder [Jasnoski et al., 1994; Ramesh etal., 1991; Schmidt-Traub and Bamler, 1997], socialanxiety [Bell et al., 1990, 1993], and in children withinhibited temperament [Kagan et al., 1991; Rosenbergand Kagan, 1989] and attention deficity/hyperactivitydisorder [Roth et al., 1991; Marshall, 1989]. Althoughan association between allergic disorders and emo-tional symptoms has been reported in the clinical lit-erature, the nature of the relationship remains un-clear.

Notions that atopic disorders cause behavioral symp-toms can be found in the clinical allergy and immunol-ogy literature. “Allergic irritability syndrome” was pos-ited to mimic hyperactive and oppositional behaviors insome children, and allergy treatment claimed to calmthe behavioral symptoms [Klein et al., 1985]. Similarly,food allergies are posited to cause hyperactivity orother disruptive behavioral disorders in a small subsetof children [Egger et al., 1985; Feingold, 1975].

Examples of atopic disorders predisposing people tohave behavioral symptoms include the association ofasthma and panic disorder. The explanation proposedis that the repeated experience of “air hunger” or in-creased levels of carbon dioxide can trigger a sense ofpanic [Gorman et al., 1989]. Sequelae of having achronic atopic disorder, such as separations requiredby hospitalizations, loss of school participation, traumaof intubations, and self-esteem issues engendered bydisfiguring rashes or steroid side effects can all lead toemotional problems in children [Nocon, 1991]. Addi-tionally, some of the medications used to treat atopicdisorders, such as oral steroids, can cause anxiety,sleep disturbance, mild-moderate cognitive dysfunc-tion, and affective symptoms [Bender and Milgrom,1995].

There is evidence that certain immune mediators,notably cytokines, can trigger symptoms similar to de-pression, such as lethargy, difficulty with concentra-tion, and decreased sleep and appetite [Bell et al., 1992;Dantzer et al., 1998; Kelley et al., 1997]. It is generallyaccepted that immune responses may polarize into twodifferent cytokine environments. Type I cytokines rep-resent immune responses that are proinflammatoryand stimulate cell mediated immunity. Type II re-sponses, in contrast, are antiinflammatory and are in-volved in the generation of antibody-mediated immuneresponses. Presumably, allergic reactions would re-lease cytokines that might then lead to depressivesymptoms. Thus far there is little evidence that Type IIcytokines induce depressive symptoms. Maes and col-leagues hypothesize that depression itself may be aninflammatory process [Maes, 1993; Maes et al., 1992].Depressed patients have higher blood levels of mono-cytes, memory T cells, IL-2 receptor bearing cells, panT, pan B and T suppressor/cytotoxic cells, and in-creased T helper/suppressor ratios than patients withdysthymia, who are in turn higher than controls. Someof these immune mediators have been implicated in theinitiation or exacerbation of an atopic reaction.

Finally, it is possible that atopy and behavioral dis-orders share a common etiology, either environmentaland/or genetic in nature. Environmental factors thatcould conceivably influence both disorders include fam-ily interactional processes, toxins, light or humiditychanges, and infectious diseases. Several investigatorshave demonstrated that parent-child conflict is associ-ated with the outcome of asthma in children [Her-manns et al., 1989; Schobinger et al., 1992; Strunk etal., 1985; Wamboldt et al., 1995]. Parental criticismand parent-child conflict have also been shown to berisk factors for depression and behavioral disorders inchildren [Asarnow et al., 1993, 1994; Vostanis et al.,1994]. Thus, parental criticism is associated with bothasthma and depression in children and is a potentialcommon environmental etiologic factor for both disor-ders. In support of a genetic relationship, biologic rela-tives of inhibited children have been shown to havehigher rates of hay fever [Kagan et al., 1991], and rela-tives of children with severe asthma have been re-ported to have high rates of affective spectrum disor-ders [Wamboldt et al., 1996]. In a community sample ofschool age children, the cross correlation of atopic dis-orders in one twin and behavioral symptoms in thecotwin was primarily explained by common genetic fac-tors [Wamboldt et al., 1998].

The use of quantitative genetic analytic methodolo-gies with twin data is ideally suited to address both thequestion of common etiology and to ascertain whetherthe common etiology was primarily genetic or environ-mental in nature [Martin et al., 1997; Neale and Car-don, 1992]. If the behavioral genetic analysis showedthat most of the association of atopic disorders and be-havioral symptoms were due to unshared environmen-tal effects, then it is most likely that the sequelae of oneillness leads to the other. If, on the other hand, therewas a familial association of the disorders, then geneticor shared environmental variance could be appor-tioned.

The aim of this study was to investigate the associa-tion of atopic disorders and depression in a large popu-lation-based sample of adult twins. The specific goalswere to (1) establish the covariance of atopic disordersand depressive symptoms in monozygotic (MZ) and di-zygotic (DZ) twins in an existing adult twin sample and(2) determine whether any of the covariance resultedfrom common genetic vulnerability or shared environ-mental effects.

MATERIALS AND METHODSSubjects

The Finnish Twin Cohort consists of all Finnish twinpairs of the same gender born before 1958 with bothcotwins alive in 1967 [Kaprio et al., 1990] who wereselected from the Central Population Registry of Fin-land in 1974 and gave their signed informed consent toparticipate. The study was approved by the appropri-ate ethical committees. In 1990 a questionnaire con-sisting of 103 multiple choice questions was mailed totwin pairs who were born between 1930 and 1957(N417,876 twin individuals); 77.3% responded. Sev-eral prior reports provide more details on the sample[Hublin et al., 1994; Kaprio et al., 1996].

Allergy and Depression in Adult Finnish Twins 147

Twin zygosity was determined by examining the re-sponses of both members of each twin pair to two ques-tions on the similarity of appearance. The validity ofthe questionnaire method of zygosity was studied in asubsample by using 11 blood markers [Sarna et al.,1978]. Some 93% of all respondent pairs could be clas-sified as MZ or DZ with only slight probability of mis-classification (1.7%).

For this study, there were 554 pairs of MZ maletwins; 783 pairs of MZ female twins; 1,111 pairs of DZmales, and 1,395 pairs of DZ females, for a total sampleof 3,843 twin pairs, or 7,686 individual subjects. Meanage of the sample in 1990, with SE, was 44.4 ± 0.1 yearsfor males and 43.3 ± 0.1 years for females; the rangewas 33–60 years.

Measures

Beck Depression Index (BDI) [Beck et al.,1961]. This questionnaire asks respondents to de-scribe themselves “right now” on 21 items relating tosymptoms on a 0 to 3 intensity scale. It has become oneof the most widely used instruments for detecting de-pression in normal populations [Steer et al., 1986; Var-jonen et al., 1997]. The standard scoring of the BDI isthat total scores over 18 indicate moderate depression[Beck et al., 1988].

Atopy Score. The atopy score was derived fromquestionnaire responses as to whether the person hadever had a physician diagnosis of asthma, hay fever, oreczema. Each item was given one point if present, for apossible range in atopy scores of 0–3. Although theitems exhibit face validity, they are clearly a crude ap-proximation of atopic tendency and are not normallydistributed.

Data Analysis

Lifetime prevalence rates of asthma, hay fever andeczema, and total BDI and atopy scores, were com-pared by zygosity and gender groups using x2 statisticsor paired t-tests. Since depression had been correlatedto increased age in other samples [Zung et al, 1993],the BDI was regressed against age and found to bestatistically significant (F ratio 4 50.45; P <.0001).Thus, the raw total BDI scores were corrected for agebefore being used in the analysis. One-way analysis ofvariance tests were used to examine the rates of mod-erate depression in each of the atopy groups (0–3 atopicdisorders), as well as in the cotwins of each of the atopygroups.

To formally estimate the genetic and environmentalinfluences on atopic illnesses and depression, struc-tural equation modeling was used. Expected covari-ance matrices for MZ and DZ twins were specified,based on an additive genetic correlation of 1.0 for MZtwins and 0.5 for DZ twins, a nonadditive genetic cor-relation of 1.0 in MZ and 0.25 in DZ twins, and theshared environmental correlation of 1.0 for all twins.These models were then fit to the data using the mod-eling program Mx [Neale, 1995]. After the appropriatemodels were determined for each univariate analysis,bivariate models specifying common and specific fac-tors were applied to atopy and BDI using the Choleskymodeling approach [Loehlin, 1996].

To test the significance of a particular parameter,that is, whether the association between the two vari-ables was due to common genetic or unshared environ-mental factors, a series of reduced models were fit.These models tested whether the common additive ge-netic pathway or the unshared environmental factorcould be omitted from the model by setting the commonpaths to zero. Significance was determined by the dif-ference in x2 between the full and the reduced models.This difference is distributed as a x2 and consequently,probability levels for the significance of change inmodel fit can be obtained. A model parameter was con-sidered to be significant if its omission resulted in adecrement in the fit of the model at the 0.05 level ofsignificance based on the x2 test. The Akaike Informa-tion Criterion also was examined to determine theoverall best fitting model [Martin et al., 1997].

RESULTSTable I lists the descriptive statistics for atopic ill-

nesses and depression for this sample. The rates ofasthma are the same for males and females; the ratesfor eczema, hay fever, and depression are higher forfemales than males. Although these prevalence ratesfor asthma are lower than reported in Australia, NewZealand, or the United States, they are in the rangereported in other Scandinavian populations [Anony-mous, 1996]. No significant differences were foundcomparing MZ with DZ twins on atopy or BDI scores.

The correlations between asthma, hay fever, eczema,and depression (BDI) within and between twins in eachof the gender and zygosity groups is presented in TableII. All of the correlations are lower than one wouldpredict from prior literature. For example, the pheno-typic correlation of asthma and hay fever ranges from0.12 in MZ males to 0.27 in DZ males. In the Australiantwin sample phenotypic correlations between asthmaand hay fever ranged from 0.40–0.52 [Duffy et al.,1990]. The discrepancy in this Finnish sample is mostlikely due to two things: the very low prevalence rate ofasthma in Scandinavians and the relatively crude mea-surement of atopy.

In the entire sample, 58 subjects reported a BDIscore of over 18. The rates of subjects reporting at leastmoderate depression were significantly higher forthose subjects with three atopic disorders comparedwith subjects with fewer than three atopic disorders

TABLE I. Descriptive Statistics

Men(N 4 3330)

Women(N 4 4356)

Atopic illnessesa

% with asthma 2.8 2.8% with hayfever 11.8 14.2**% with eczema 11.8 20.7***Depressiona

% mildly depressed 12.6 19.5***% moderately depressed 2.0 3.6***Mean BDI scoreb 4.33 ± 0.08 5.60 ± 0.09***

aProportions in each gender group were compared with chi-square statis-tics.bMean scores and standard errors are reported. Gender groups were com-pared with t-tests.**P < .01; ***P < .0001.

148 Wamboldt et al.

(10% versus 2–4%; x2 4 22.77; P<.0001). Even moreinteresting, the rates of moderate depression scores ofthe cotwins of subjects with at least three atopic disor-ders were also significantly higher than cotwins of sub-jects with fewer atopic disorders (rates of moderate de-pression 8.6% versus 2.7–3.9%; x2 4 9.38; P < .02).This is despite the fact that in the entire sample, onlyone twin pair was concordant for having three atopicdisorders. There were no statistically significant differ-ences in depression scores between the cotwins of MZand DZ twins with three atopic disorders. Nonetheless,this finding suggested a familial relationship betweenatopic disorders and depressive symptoms, so furtherstatistical modeling was performed.

Univariate modeling of both atopy and BDI was per-formed first. The univariate analysis of atopy tested amodel involving additive genetic (A), shared environ-

mental (C) and unshared environmental (E) factors, orthe ACE model, as well as a model involving nonaddi-tive genetic (D) factors rather than shared environmen-tal influences (ADE). Neither of these models fit thedata (see Table III). However, when a gender effect(determined to be a scalar equal to 1.167, a fixedamount that was multiplied with the female covariancematrixes to take account of the significantly higherphenotypic variances among women than among men)was included in either model, they both fit well. Sharedenvironmental influences were nonsignificant as therewas no x2 change when C was dropped from the ACE/scalar model. Although the model including the nonad-ditive genetic effects fit the data, the effect was consid-ered not to be statistically significant in the model (x2

change of 1.66, df 4 1, when D was dropped from theADE model). Thus, the main univariate determinantsof the atopy score were additive genetic and nonsharedenvironmental factors. These results are consistentwith others examining the genetic and environmentalunderpinnings of atopic illness using twin models[Duffy et al., 1990; Edfors-Lubs, 1971; Harris et al.,1997; Jenkins et al., 1997; Laitinen et al., 1998; Licht-enstein and Svartengren, 1997; Nieminen et al., 1991].

Univariate modeling of the BDI data first tested theACE and ADE models. Both of these models were sig-nificantly different from the data (see Table IV). Whena scalar effect for gender differences was included inthe models, the ACE model still failed, but the ADEmodel fit the data well. Again, the scalar effect tookaccount of the higher variance among women thanamong men. Nonadditive genetic effects were neededfor the model, as not only did the AE model not fit, butthe difference in x2 between the ADE model and the AEmodel was significant (x2 change of 11.88, df 4 1, P <.005). Thus, the main univariate determinants of theBDI score were broad genetic and unshared environ-mental factors, consistent with other findings in theliterature [Hewitt et al., 1997; Kendler et al., 1994].

Based on the above univariate results, bivariatemodels specifying AE latent factors for atopy, ADE la-tent factors for BDI, and common AE factors relating toboth atopy and BDI were tested, with results shown inTable V. Scalars for gender differences were included

TABLE II. Correlation Matrixes by Gender and Zygosity

Variable Dep1 Atopy1 Dep2 Atopy2

MZ males (N 4 554)Dep1 1.000Atopy1 0.074 1.000Dep2 0.380 0.089 1.000Atopy2 0.007 0.300 0.134 1.000DZ males (N 4 1111)Dep1 1.000Atopy1 0.070 1.000Dep2 0.116 0.060 1.000Atopy2 0.049 0.089 0.062 1.000MZ females (N 4 783)Dep1 1.000Atopy1 0.074 1.000Dep2 0.432 0.082 1.000Atopy2 0.039 0.297 0.096 1.000DZ females (N 4 1395)Dep1 1.000Atopy1 0.105 1.000Dep2 0.156 0.066 1.000Atopy2 0.033 0.145 0.114 1.000Variable Asthm1 Derm1 Hayf1 Asthm2 Derm2 Hayf2MZ males (N 4 554)Asthma1 1.000Derm1 0.146 1.000Hayf1 0.120 0.254 1.000Asthma2 0.215 0.041 0.014 1.000Derm2 −0.007 0.182 0.112 0.087 1.000Hayf2 0.114 0.207 0.255 0.225 0.179 1.000DZ males (N 4 1111)Asthma1 1.000Derm1 0.089 1.000Hayf1 0.226 0.190 1.000Asthma2 0.075 −0.009 0.053 1.000Derm2 −0.030 0.042 0.007 0.043 1.000Hayf2 0.055 0.087 0.081 0.271 0.266 1.000MZ females (N 4 783)Asthma1 1.000Derm1 0.092 1.000Hayf1 0.236 0.311 1.000Asthma2 0.230 −0.028 −0.045 1.000Derm2 0.140 0.262 0.172 0.093 1.000Hayf2 0.126 0.095 0.209 0.210 0.248 1.000DZ females (N 4 1395)Asthma1 1.000Derm1 0.076 1.000Hayf1 0.261 0.255 1.000Asthma2 0.090 0.051 0.064 1.000Derm2 0.015 0.099 0.047 0.143 1.000Hayf2 0.115 0.086 0.089 0.223 0.294 1.000

TABLE III. Univariate Models of Atopy*

ModelChi

square df Prob Akaike’s

ACE 97.49 9 <0.001 79.49ADE 96.44 9 <0.001 78.44AE 97.49 10 <0.001 77.49CE 126.40 10 <0.001 106.40E 263.11 11 <0.001 241.11ACE/scalar 9.77 8 0.281 −6.23ADE/scalar 8.12 8 0.422 −7.89AE/scalar 9.77 9 0.369 −8.23CE/scalar 40.57 9 <0.001 22.57E/scalar 173.75 10 <0.001 153.75

*These data are based on analysis of the entire sample of monozygotic anddizygotic twins, both male and female. The scalar refers to the need for afixed value that corrected the difference in variances between males andfemales. The model is composed of additive genetic effects (A), commonenvironmental effects (C), nonadditive genetic effects (D), and unsharedenvironmental effects (E). The best-fitting model is denoted in bold type.

Allergy and Depression in Adult Finnish Twins 149

separately for BDI and atopy. The full model describedin preceding paragraphs yielded a good fit with thedata, with an associated P-value of 0.241. When thescalar effects were forced to be equal, the fit wasequally as good, so the more parsimonious model wasused as the full model, i.e., AE factors common to bothatopy and BDI; AE latent factors for atopy; ADE latentfactors for depressive symptoms; and a single scalargender effect.

To test whether the common factors were necessary,they were each set to zero in turn. When the commongenetic factor between the two variables was restrictedto zero, the resulting change in x2 was 14.7, df 4 1,which indicates that the reduced model without a ge-

netic correlation has a significantly worse fit (P < .005).When the unshared environmental correlation be-tween the two phenotypes was dropped, the resultingfit was statistically different from the full model (x2 44.89 with 1 df; P < .05.) Thus, although the covarianceoverall between atopic disorders and BDI score issmall, both the additive genetic and the specific envi-ronmental covariances are necessary for the best-fitting model. Model fit statistics can be seen in Ta-ble V.

The full model with standardized pathway scores isillustrated in Figure 1. In this study the heritability ofatopy was equal to 0.29 (95% CI 0.25–0.33), which wassignificantly lower than that reported in other studieswhere heritability ranges from 0.36–0.72, presumablybecause the self report questionnaire is not as accurateas in those studies where examination of the patientswas done [Sanford et al., 1996]. The heritability of de-pression was 0.42 (95% CI 0.37–0.46). The phenotypiccorrelation between atopy and depression was .09. Thenarrow genetic correlation between atopic disordersand depression, calculated as (0.54)(0.11)/square root((0.542)(0.112 + 0.302)), was equal to 0.34. Thus, addi-tive genetic effects account for 64% of the covariancebetween atopy and the BDI; these additive genes arecorrelated 0.34. These results support the hypothesisthat there is some shared genetic covariance betweenatopic disorders and depressive symptoms.

Secondary Analyses

Due to the lack of normality in both the BDI scoresand the atopy scores, concerns could be raised aboutperforming the above types of analyses. Similarly, thelow correlations between atopic conditions, as notedabove, may indicate that the atopic conditions shouldnot be subsumed into a quasi-continuous scale. To ad-dress these concerns, the analysis was replicated witha newer technique of analysis of comorbid conditions intwins, as described by Neale and Kendler [1995], andwith an Mx statistical program implemented by PakSham, M.D. (personal communication, 1999). In thismodel, the comorbidity of two nonnormally distributedillnesses could be looked at in twins. Twins can be co-morbid for neither, both, one, or a mixture of the twoconditions. If MZ twins have higher rates of comorbid-ity of the two conditions than DZ twins, there is evi-dence of a genetic association. This technique sets the

TABLE IV. Univariate Models of the Beck Depression Index(Age Corrected)*

ModelChi

square df Prob Akaike’s

ACE 116.30 9 <0.001 98.30ADE 105.07 9 <0.001 87.07AE 116.30 10 <0.001 96.30CE 188.69 10 <0.001 168.69E 390.50 11 <0.001 368.50ACE/scalar 26.04 8 <0.001 10.04ADE/scalar 14.16 8 0.078 −1.84AE/scalar 26.04 9 0.002 8.04CE/scalar 97.86 9 <0.001 79.86E/scalar 293.21 10 <0.001 273.21

*These data are based on analysis of the entire sample of monozygotic anddizygotic twins, both male and female. The scalar refers to the need for afixed value that corrected the difference in variances between males andfemales. The model is composed of additive genetic effects (A), commonenvironmental effects (C), nonadditive genetic effects (D), and unsharedenvironmental effects (E). The best-fitting model is denoted in bold type.

TABLE V. Bivariate Models of Atopy and Beck DepressionIndex (BDI) (Age Corrected)*

ModelChi

square df Prob Akaike’s

Full model: 36.14 31 0.241 −25.86AE for atopy/ADE for BDI;

scalars for gendereffects

Drop D for BDI 49.44 32 0.025 −14.56Full model, but constrain

gender scalar effects tobe equal

36.16 32 0.280 −27.84

Full model, constraingender scalar effects tobe equal and dropcommon A

50.86 33 0.024 −15.14

Full model, constraingender scalar effects tobe equal and dropcommon E

41.04 33 0.159 −24.96

Full model, constraingender scalar effects tobe equal and drop allcommon factors

4181.24 34 <0.001 4113.24

*The full model tested consisted of specific additive genetic (A), nonaddi-tive genetic (D) and unshared environmental effects (E) for BDI; additivegenetic and specific environmental effects (AE) for atopy; and additivegenetic and unshared environmental effects (AE) effects common to bothatopy and depression. The scalars adjust the gender differences in vari-ances for each atopy and BDI. Each successive model then deleted one ofthe parameters to test whether there was a significantly worse fit whenthat parameter was deleted. The best-fitting model has the lowest Akaike’scriteria and is denoted in bold type.

Fig. 1. The best-fitting model of genetic, shared, and unshared envi-ronmental factors influencing atopy and Beck Depression Index scores inFinnish adult male and female twins. A scalar to compensate for largervariances in scores was applied and was equal to 1.167. The circles repre-sent latent factors: “A” represents additive genetic effects, “D” representsnonadditive genetic effects, and “E” represents unshared environmentaleffects. The efficients represent the standardized path.

150 Wamboldt et al.

thresholds for prevalence rates separately for each gen-der, based on the sample prevalence rates, which wouldsubsume the need for the “gender scalar” effect thatwas modeled above. For this analysis, twins were codedas having either no or at least one atopic condition, andas having a BDI score below (no depression) or above(positive for depression) the clinical BDI cut-off scorefor moderate depression. Thus, this model is slightlydifferent from the earlier one, in that we are modelingonly presence or absence of an atopic disorder; thismodel does not take into account the difference be-tween having one or more atopic disorders. If anything,it should be a more stringent test of the hypothesis.The bivariate analyses of any atopic condition with atleast moderate depression were then carried out as perNeale and Kendler [1995]. The results are shown inTable VI.

The same initial full model was used as before: ADEinputs for depression, and AE inputs for atopy. As canbe seen in Table VI, this model does not quite fit thedata, with a P-value of 0.043. However, once the com-mon D pathway, or shared nonadditive genetic effects,is deleted, the model fits nicely, with a P-value of 0.053.If the common A (additive genetic) or E (unshared en-vironmental) pathways are separately dropped, themodels do not fit (P < 0.05). If both the common D andcommon E pathways are dropped, leaving a model thatshares only common additive genetic covariance, themodel fits even better, with a P-value of 0.057, and anAikake’s value of −13.706. Since this model is not asignificantly worse fit than the shared A and E path-ways, and since it is the most parsimonious model, ityields the best fit to the data. Within this model, theentire covariance of any atopic disorder with depres-sion is explained by additive genetic effects. The phe-notypic correlation is 0.12; and the narrow genetic cor-relation is 0.475. Thus, results are similar to the aboveanalyses.

DISCUSSIONThis study adds to the literature supporting an as-

sociation between atopic disorders and depressivesymptoms in adulthood. In this sample the overall co-variance between history of allergic disorders and de-pression was small, approximately 10–12%. However,the measures used to ascertain allergic status were

very crude, and the depression measure was one of cur-rent symptoms, not lifetime occurrence. Despite thesmall covariance, there appeared to be a familial rela-tionship between number of allergic disorders and de-pression. This was suggested by the significantlyhigher rates of moderate or severe depression in thecotwins of those twins who had at least three atopicdisorders. If the depression was simply a consequenceof having numerous medical problems, there would beno reason for the cotwin also to have increased rates ofdepression. However, it is possible that the finding ofincreased depression among the cotwins of highlyatopic probands might be explained by their having oneor two severely atopic conditions themselves, or bysharing a genetic predisposition to depression withtheir twins, who are reporting depressive symptomsbecause she or he suffers from a chronic illness. It ispossible that there is a phenotypic causation here, i.e.,atopic conditions causing depression. More variableswould be needed to eliminate this hypothesis. By theuse of statistical modeling, it appeared that most ofthis effect was due to shared additive genetic effects.The fact that a statistically significant shared geneticeffect was found is a new and potentially importantfinding that deserves further follow-up with more pre-cise measurements.

It is important to note that this was a nonclinicalsample, and that the sample means are similar to non-clinical sample means for the BDI, with only 3% of thesample scoring in the moderately depressed range.Likewise, this was not a sample selected for atopic ill-ness: at most 25% of the individuals reported anyatopic illness. The relationship between atopy and be-havior symptoms may be different in a sample clini-cally referred for either behavior problems or atopicsymptoms. This is also suggested in the clinical litera-ture reviewed in the Introduction. It appears that thereis a small subset of patients for which this interrela-tionship of allergic symptoms and behavioral or emo-tional symptoms may be very salient.

A major advantage of this study is the large samplesize in a relatively homogenous population. A disad-vantage is the limited methods for assessing both atopyand depression. The atopy score was simply a tabula-tion of up to three diagnoses of allergic disorders. Manypeople can have atopic signs, e.g., positive skin tests orelevated IgE levels, without having enough clinicalsymptoms to elicit a clinical diagnosis of an atopic dis-order [Evans, 1993; Weeke, 1992]. Thus, this atopyscore is a relatively crude assessment. Likewise, asingle BDI score is a very limited approximation of life-time depression. With better measures of both atopicrisk and depression, the correlation of the two wouldperhaps be higher, as was found in a smaller samplewith better measures of both depression and atopy[Wamboldt et al., 1998]. Further research should em-ploy multimethod assessment of psychological symp-tomatology as well as laboratory assessment of some ofthe atopy profiles, e.g., IgE level, skin testing, or ge-netic markers.

In conclusion, this study presents data from a largesample of Finnish adult twins, where an associationwas found between self-reported indices of atopic ill-

TABLE VI. Model-Fitting Using Comorbidity Technique*

ModelChi

square df Prob Akaike’s

Full model: AE for atopy/ADEfor BDI

38.147 24 0.034 −9.853

Drop common D pathway 37.420 25 0.053 −12.580Drop common A pathway 38.481 25 0.042 −11.5191Drop common E pathway 38.675 25 0.040 −11.325Drop common D and common E

paths38.294 26 0.057 −13.706

Drop common A and common Dpaths

42.074 26 0.024 −9.926

Drop all common paths 49.301 27 0.006 −4.699

*The presence of at least one atopic condition with at least moderate de-pression in the Finnish twin sample was analyzed. Thresholds for preva-lence rates were set separately for males and females, but constrained to beequal across zygosity groups. The best-fitting model is denoted in bold type.

Allergy and Depression in Adult Finnish Twins 151

ness and depression. Using quantitative genetic mod-eling, it was shown that the majority of the associationwas likely due to common genetic effects, suggestingnew avenues of research into the etiologies and treat-ments of both disorders.

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