Soc Psychiatry Psychiatr Epidemiol DOI 10.1007/s00127-014-0885-1

ORIGINAL PAPER

Bipolar disorder and parental psychopathology Dan Sucksdorff • Roshan Chudal • Auli Suominen • Elina Jokiranta • Alan S. Brown • Andre Sourander

Received: 16 October 2013 / Accepted: 14 April 2014  Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose Few population-based studies have examined the association between parental psychopathology and bipolar disorder (BPD) in offspring. One limitation is lack of control for potential confounding by indicators of parental socio-economic status or maternal smoking during pregnancy. Furthermore, none of them included analyses restricted to parental diagnoses received prior to the birth of the offspring. Associations could not be affected by child-related factors affecting the parent in such analyses. This study explores associations between those parental psychiatric disorders diagnosed at any point of time as well as those diagnosed before offspring birth, and BPD in offspring. Methods In this nested case–control study, we identified 1,861 cases, age up to 25 years, 3,643 matched controls, and their parents from Finnish national registers. The

D. Sucksdorff (&)
R. Chudal
A. Suominen
E. Jokiranta
A. Sourander Department of Child Psychiatry, Faculty of Medicine, Research Centre for Child Psychiatry, Institute of Clinical Medicine, University of Turku, Lemminka¨isenkatu 3/Teutori (3rd floor), 20014 Turku, Finland e-mail: [email protected] A. S. Brown
A. Sourander Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, USA A. S. Brown Department of Epidemiology, Columbia University, Mailman School of Public Health, New York, USA A. Sourander Department of Child Psychiatry, Turku University Hospital, Turku, Finland

associations were examined using conditional logistic regression, calculating odds ratios (OR) and adjusting for region of birth, parental age and education and mother’s smoking during pregnancy. Results Anytime diagnosed parental disorders associating with BPD in offspring (95 % confidence interval) were BPD [OR (maternal) 5.2 (2.52–10.62); OR (paternal) 8.1 (3.77–17.26)], schizophrenia and related psychoses [OR (maternal) 3.1 (1.69–5.84); OR (paternal) 4.5 (1.97–10.27)], other affective disorders [OR (maternal) 3.0 (2.08–4.21); OR (paternal) 3.0 (1.97–4.47)] and maternal anxiety disorders OR 2.6 (1.08–6.42). Statistically significant associations were also found for parental schizophrenia and related psychoses, and other affective disorders, diagnosed before offspring birth. Conclusions BPD is associated with many parental psychiatric disorders, particularly BPD and schizophrenia and related psychoses. The associations must be partially due to child-independent factors. Covariate adjustments had only a minor impact on the associations. Keywords Bipolar disorder
Schizophrenia
Register
Population-based study
Epidemiology
Parental psychopathology

Introduction Bipolar disorder (BPD) shows a pattern of familial aggregation with other psychiatric disorders. Clinical studies have reported high rates of psychopathology, particularly mood and disruptive behavior disorders, in the offspring of parents with BPD [1–6]. In a meta-analysis, the offspring of bipolar parents was four times more likely to suffer from a mood disorder and almost three times more likely to

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Soc Psychiatry Psychiatr Epidemiol

suffer from any mental disorder compared to the children of healthy parents [7]. However, clinical studies are limited by small to modest sample sizes and potential selection bias due to the study design. To our knowledge, seven population studies based on nationwide registers have examined the association between BPD and psychopathology in parents, showing a markedly elevated risk for BPD in the offspring with a history of parental BPD [8–14]. Five of them showed that parental schizophrenia was a risk factor for BPD [8–10, 12, 14]. Another study found an association between BPD and a parental diagnostic group that included schizophrenia and other nonaffective psychoses [11]. Furthermore, the risk of BPD in the offspring was markedly elevated when both parents had BPD, or when one parent had BPD and the other schizophrenia, compared to offspring with only one parent having BPD and the other parent being healthy [12]. Additional parental disorders shown to associate with BPD are schizoaffective disorder [8, 9], acute and transient psychotic disorders [14], recurrent depression and other affective disorders [8]. The population-based studies have varied in terms of case ascertainment and the parental psychiatric diseases studied. The generalizability of the results of the previous population-based studies could be limited by the fact that six out of seven of these studies were conducted in the same country, Denmark, with partially overlapping population samples. Although the findings were novel and important, case selection in the Swedish study [10] was restricted to inpatient diagnoses. The knowledge of whether the BPD risk in the offspring varies depending on the sex of the affected parent is limited with four populationbased studies reporting results separately for mothers and fathers [8, 9, 13, 14]. Similar to our study, three of them [8, 9, 14] examined the full range of parental psychiatric disorders in relation to BPD in the offspring, but included fewer parental diagnostic categories compared to our study. Only three previous population-based studies adjusted for the effects of confounding by age of the mother and the father at the time of birth [8, 9, 13]. No previous population-based study has adjusted for smoking during pregnancy or any indicators of parental socio-economic status, i.e., education, income or occupation. Finally, none of these studies examined the associations between BPD in offspring and parental psychiatric disorders restricted to diagnoses given prior to the birth of the offspring. This approach would not allow for the associations to be influenced by child-related factors affecting the parent. Particularly, if BPD in the offspring is found to be associated with parental schizophrenia and related psychoses in such an analysis, it would offer further support for mounting studies indicating a genetic link between BPD and these disorders.

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The aim of this study is to examine associations between BPD in the offspring and maternal vs. paternal psychopathology covering the full range of parental mental disorders while controlling for several potential confounders. A subanalysis limited to parental psychiatric diagnoses given before the birth of the offspring was included in the study. Based on the findings from previous studies, we hypothesized that BPD in the offspring is associated with parental affective disorders and schizophrenia and related psychoses.

Materials and methods Study design Our study is part of the Finnish Prenatal Study of Bipolar Disorders (FIPS-B), which is a nationwide populationbased case–control study capitalizing linkages between various national registers. The FIPS-B utilizes a nested case–control design and is based on all singleton live births in Finland between January 1, 1983 and December 31, 1998 (n = 1,009 846). The cases were identified from the Finnish Hospital Discharge Register (FHDR), which is maintained by The National Institute for Health and Welfare (THL). The matched controls, along with parents of cases and controls, were identified by linking the Finnish Central Population Register to the FHDR. The linkage between registers is made possible by the personal identification number (PIN), which is assigned to all Finnish residents and is unique for each person. This study has been authorized by the Ministry of Social Affairs and Health in Finland. The ethics committee of the hospital district of Southwest Finland, THL and the Institutional Review Board of the New York State Psychiatric Institute have given approval for the study. The full description of the study design and data sources is available [15]. National registers In Finland, medical diagnoses are routinely registered in the FHDR. Starting from 1969, the FHDR covers all inpatient care units in Finland; somatic and psychiatric hospitals, inpatient wards of local health centers, military wards, prison hospitals and private hospitals. Since January 1, 1998, the FHDR also includes outpatient care in public specialized hospital units. All diagnoses are based on the International Statistical Classification of Diseases (ICD): ICD-8 from 1969 to 1986, ICD-9 from 1987 to 1995 and ICD-10 from 1996 onwards. The Finnish Central Population Register is maintained by the Finnish Population Register Centre and local register offices and includes basic information, such as name,

Soc Psychiatry Psychiatr Epidemiol

PIN-code, birth municipality and family relations, about Finnish citizens and people residing permanently in Finland. The Finnish Medical Birth Register (FMBR), established in 1987 and maintained by THL, includes comprehensive and standardized data on the perinatal period on all births in Finland. Data include demographic characteristics, reproductive history, maternal health-related behaviors, complications during pregnancy and perinatal events. In this study, the purpose of the FMBR was to collect information on maternal smoking during pregnancy. Statistics Finland is a public authority for various statistical services. It provided this study data from 1995 on educational level of the parents of cases and controls.

schizoid personality disorder; ICD-9 diagnoses 2962A-G/ 2963A-G/2964A-G/2967A BPD, 295 schizophrenic psychoses, 297 paranoid states, 298 psychoses aliae, 3010A paranoid personality, 3012A schizoid personality and 3012C schizotypal personality. All cases were first matched to two controls (N = 3,722) on gender and date of birth ±30 days. Among controls, 79 belonging to a twin birth were excluded resulting in a total of 3,643 controls. The matched control was required to be alive and living in Finland on the day the case was diagnosed. Date of birth was included as a matching factor to control for secular changes in prevalence of exposures and to control for potential confounding by season of birth. The controls were identified through linkage between the FHDR and the Finnish Central Population Register.

Identification of cases and controls Maternal and paternal psychiatric disorders The cases consist of persons (N = 1,861) born between 1983 and 1998 and according to the FHDR diagnosed with BPD by December 31, 2008 (age range up to 25 years). They were identified based on ICD-9 codes 2962A-G, 2963A-G, 2964A-G and 2967A and ICD-10 codes F31x. The most recent diagnosis was used for identification. A manual verification was conducted for those who also had schizophrenia (ICD-10 code F20) or schizoaffective disorder (ICD-10 code F25) diagnosed at some time point. We found 54 individuals with both schizophrenia and BPD diagnoses, 70 individuals with schizoaffective disorder and BPD diagnoses, and 16 individuals with schizophrenia, schizoaffective disorder and BPD diagnoses. Individual assessment was then carried out by two investigators, A.S. (Andre Sourander) and A.B. (Alan Brown), whereby an agreement was reached on the diagnosis. Out of 54 individuals with schizophrenia and BPD diagnoses, 17 were classified as schizophrenia, 10 as BPD cases and 27 were excluded. Among 70 individuals with schizoaffective disorder and BPD diagnoses, 22 were classified as schizoaffective disorder, 30 as BPD cases and 18 were excluded. Out of 16 individuals with all three diagnoses, schizophrenia, schizoaffective disorder and BPD, one was classified as schizophrenia and seven as schizoaffective disorder, while the rest were excluded from the study. The controls were defined as persons without BPD, schizophrenia or diagnoses related to these disorders: ICD10 diagnoses F30 single manic episode, F31 BPD, F34.0 cyclothymia, F38.0 other mood disorders; mixed affective episode, F39 unspecified mood disorder, F20–29 (schizophrenia, schizotypal disorder, persistent delusional disorders, acute and transient psychotic disorders, induced delusional disorder, schizoaffective disorders, other nonorganic psychotic disorders, unspecified non-organic psychosis), F60.0 paranoid personality disorder and F60.1

Mothers and fathers were identified from the Finnish Central Population Register. The father was assumed to be the husband of the mother at the time of the child’s birth. In case of unmarried mothers, the paternity was confirmed by acknowledgment of the father. Furthermore, DNA testing for paternity is available free of charge provided that the father agrees to such testing. The paternity was established in 97.9 % of the cases and 98.9 % of the controls included in this study. Mothers and fathers identified from the Finnish Central Population Register were then linked to the FHDR from which parents’ psychiatric diagnoses were obtained. The parents were followed up starting from 1969 to the end of 2009. Parental psychiatric diagnoses were classified into seven categories (‘‘Appendix’’). Categories one to six were: Schizophrenia and related psychoses; bipolar disorder; other affective disorders; anxiety disorders; other neurotic and personality disorders and other nonpsychotic disorders; alcohol and drug addiction/abuse. Each parent was assigned to only one diagnostic category in a hierarchical manner. For example, if the parent had been diagnosed with both BPD and schizophrenia, she/he was assigned to the category of schizophrenia and related psychoses. Similar categorizations have been used in previous studies [16–18]. The seventh category, disorders usually diagnosed in childhood or in adolescence, was examined separately. Therefore, a parent diagnosed with a disorder belonging to this category (e.g., ADHD, autism spectrum disorder) could also belong to one of the six previously described categories. The separate analysis makes it possible to isolate the association for these early-onset disorders. To enable further analyses, we then divided the first category, schizophrenia and related psychoses, into three subcategories in the following hierarchical order:

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schizophrenia; schizoaffective disorder; other nonaffective psychoses (‘‘Appendix’’). Confounding factors Advancing paternal [19, 20] and maternal [20] ages at conception have been shown to associate with BPD in the offspring. Significant regional differences have been seen in the prevalence of psychiatric disorders [21], schizophrenia [22] and the use of psychiatric hospital beds [23] in different geographical areas of Finland. Higher educational level of parents may be associated with increased risk of BPD in the offspring [24]. No previous population-based study that we know of has examined the association between maternal smoking during pregnancy and BPD in the offspring. However, it is well documented that smoking can cause fetal growth retardation [25–28] and this together with being born preterm has been reported to associate with BPD [29]. Information on parental age at the time of birth of the offspring and region of birth of cases/controls was obtained from the Finnish Central Population Register. The Statistics Finland provided information on parental education. Information on maternal smoking during pregnancy was obtained from the FMBR. It was collected by maternity clinic nurses on routine obstetric visits during the second trimester of pregnancy and documented in health records. Data on maternal age at the time of birth of the offspring were available for all cases and controls. Due to unknown paternity, data on paternal age at time of offspring birth were unavailable for 2.1 % of the cases and 1.1 % of the controls. Maternal age was classified into following categories: \20, 20–24, 25–29, 30–34, 35–39 and C40 years. Corresponding categories for paternal age were: \20, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49 and C50 years. The birth municipality information was available for all cases and controls and was used to group the study sample into four regions in Finland. The four regions, based on population data from Statistics Finland, were: southern Finland (which includes the capital city Helsinki), western Finland, eastern Finland and northern Finland. Parental educational level was based on their educational status at the end of 1995. We classified the parental educational level into four categories: (1) Master/Licentiate/Doctoral degree, (2) University/Polytechnics bachelor degree, (3) upper secondary school/equivalent vocational degree and (4) basic education (comprehensive school). Paternal educational level data were not available for 2.1 % of the cases and 1.1 % of the controls. Information on maternal smoking during pregnancy was available from 1987 onwards.

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Statistical methods The selection of covariates to be included in the adjusted models was based on bivariate analyses testing the significance of the association between covariates and parental psychiatric diagnoses in controls, and between covariates and BPD in the offspring (Table 1). We tested six covariates with a two-sided significance limit of p \ 0.10: Maternal and paternal age, region of birth, maternal and paternal education and maternal smoking during pregnancy. Conditional logistic regression was used to examine the association between parental psychiatric diagnoses and BPD in the offspring. First, we calculated the unadjusted odds ratios (OR) with 95 % confidence intervals for all maternal and paternal diagnostic categories (and subcategories). p values were calculated by Wald’s v2–test with a two-sided significance limit of p \ 0.05. We then adjusted for the six covariates described above. Statistical analyses were performed with SAS statistical software (SAS Version 9.3; SAS Institute Inc., Cary, NC).

Results Table 1 shows, that all potential covariates tested, including maternal and paternal age, region of birth, maternal and paternal education and maternal smoking during pregnancy have significant or near-significant associations to both maternal and paternal psychiatric diagnosis and BPD in offspring. Table 2 shows the associations with BPD in the offspring when mother, father or both parents have any psychiatric diagnosis. All of the associations quantified using odds ratios (OR) with 95 % confidence interval (CI), are statistically significant. The adjusted OR (95 % CI) for any psychiatric diagnosis in mothers is 2.79 (95 % CI 1.97–3.94), in fathers 2.50 (95 % CI 1.81–3.46) and in both parents 5.36 (95 % CI 3.03–9.46). Table 3 presents the distribution of parental psychiatric disorders among the cases and the controls. In addition, it depicts the results of associations between parental psychiatric disorders, diagnosed at any time point, and BPD in the offspring when compared with controls. According to the adjusted analyses, BPD in offspring is associated with parental BPD [OR (maternal) 5.17 (95 % CI 2.52–10.62); OR (paternal) 8.07 (95 % CI 3.77–17.26)], schizophrenia and related psychoses [OR (maternal) 3.14 (95 % CI 1.69–5.84); OR (paternal) 4.49 (95 % CI 1.97–10.27)], other affective disorders [OR (maternal) 2.96 (95 % CI 2.08–4.21); OR (paternal) 2.96 (95 % CI 1.97–4.47)], other neurotic and personality disorders and other nonpsychotic disorders [OR (maternal) 2.00 (95 % CI 1.11–3.60); OR

Soc Psychiatry Psychiatr Epidemiol Table 1 Covariates in relation to parental psychopathology and in relation to BPD Relationship between covariates and parental psychiatric diagnoses in controls Any maternal psychiatric diagnosis No n (%) Maternal age

Yes n (%)

p value(1)

p value(1) \0.0001

\0.0001

0.0093

\0.0001

\0.0001

\0.0001

\0.0001

0.0351

0.1075

\0.0001

0.0002

0.0038

Any paternal psychiatric diagnosis No n (%)

n = 3,167

n = 476

n = 3,121

n = 480

\20

73 (2.3)

20 (4.2)

64 (2.1)

28 (5.8)

20–24

618 (19.5)

85 (17.9)

592 (19.0)

99 (20.6)

25–29

1,115 (35.2)

164 (34.5)

1,111 (35.6)

158 (32.9)

30–34

917 (29.0)

126 (26.5)

909 (29.1)

122 (25.4)

35–39

360 (11.4)

66 (13.9)

365 (11.7)

55 (11.5)

C40

84 (2.7)

15 (3.2)

80 (2.6)

18 (3.8)

n = 3,136

n = 465

\20

17 (0.5)

20–24 25–29

Paternal age

0.0762

Yes n (%)

Relationship between covariates and BPD in offspring p value(2)

n = 3,121

n = 480

2 (0.4)

13 (0.42)

6 (1.25)

315 (10.0) 967 (30.8)

67 (14.4) 120 (25.8)

318 (10.2) 945 (30.3)

64 (13.3) 142 (29.6)

30–34

1,034 (33.0)

135 (29.0)

1,035 (33.2)

134 (27.9)

35–39

575 (18.3)

96 (20.7)

577 (18.5)

94 (19.6)

40–49

214 (6.8)

42 (9.0)

216 (6.9)

40 (8.3)

C50

14 (0.5)

3 (0.7)

17 (0.5)

0 (0)

n = 3,167

n = 476

No education after secondary school

651 (20.6)

Vocational degree or secondary school (high-school in USA) graduate College degree or bachelor university degree

Maternal education

Master or licentiate or PhD

n = 480

144 (30.3)

628 (20.1)

150 (31.3)

1,858 (58.7)

274 (57.6)

1,842 (59.0)

268 (55.8)

433 (13.7)

41 (8.6)

427 (13.7)

46 (9.6)

225 (7.1)

17 (3.6) n = 465

No education after secondary school

808 (25.8)

Vocational degree or secondary school (high-school in USA) graduate College degree or bachelor university degree Master or licentiate or PhD

224 (7.18)

16 (3.3)

n = 3,121

n = 480

147 (31.6)

787 (25.2)

168 (35.0)

1,718 (54.8)

251 (54.0)

1,705 (54.6)

264 (55.0)

291 (9.3)

41 (8.8)

305 (9.8)

27 (5.6)

324 (10.4)

21 (4.4)

319 (10.2)

26 (5.6)

n = 3,167

n = 476

Southern

1,177 (37.2)

Eastern

Region of birth

\0.0001

n = 3,121

n = 3,136

Paternal education

0.0094

0.0026

n = 3,121

n = 480

195 (41.0)

1,172 (37.6)

175 (36.5)

354 (11.2)

51 (10.7)

335 (10.7)

66 (13.8)

Western

1,119 (35.3)

170 (35.7)

1,103 (35.3)

175 (36.5)

Northern

517 (16.3)

60 (12.6)

511 (16.4)

64 (13.3)

Maternal smoking during pregnancy

0.1511

n = 1,193

n = 159

n = 1,171

n = 170

No

1,003 (84.1)

122 (76.7)

0.0199

994 (84.9)

125 (73.5)

Yes

190 (15.9)

37 (23.3)

177 (15.1)

45 (26.5)

(1)

p values were calculated by Pearson’s v2–test

(2)

Conditional logistic regression was used to examine the relationship and p values were calculated by Wald’s v2–test

(paternal) 1.93 (95 % CI 1.11–3.35)], and maternal anxiety disorders [OR 2.63 (95 % CI 1.08–6.42)]. Among the diagnostic subcategories of schizophrenia and related psychoses, statistically significant associations to BPD in

the offspring were found in the adjusted analyses for paternal schizophrenia [OR 5.01 (95 % CI 1.25–20.13)], maternal schizoaffective disorder [OR 11.49 (95 % CI 1.21–108.92)], and other nonaffective psychoses for both

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Soc Psychiatry Psychiatr Epidemiol Table 2 Frequencies, percentages and OR’s with 95 % CI’s for parental psychiatric diagnoses Case n (%)

Control n (%)

Unadjusted OR (95 % CI)

Unadjusted, subjects with complete covariate data: OR (95 % CI)

Adjusteda OR (95 % CI)

Mother, father or both parents having a psychiatric diagnosis

a

Mother yes, father no

346 (19.0)

359 (10.0)

2.76 (2.29–3.33)

3.11 (2.24–4.32)

2.79 (1.97–3.94)

Father yes, mother no Both parents

317 (17.4) 186 (10.2)

374 (10.4) 106 (2.9)

2.25 (1.87–2.70) 4.53 (3.36–6.11)

2.42 (1.77–3.29) 5.79 (3.41–9.81)

2.50 (1.81–3.46) 5.36 (3.03–9.46)

Adjusted for maternal and paternal age, maternal and paternal education, region of birth and maternal smoking during pregnancy

parents [OR (maternal) 2.40 (95 % CI 1.07–5.41); OR (paternal) 3.71 (95 % CI 1.28–10.78)]. As shown in Table 3, parental diagnostic categories failing to reach statistically significant associations with BPD in the offspring in the adjusted analyses were maternal and paternal alcohol and drug addiction/abuse, maternal and paternal disorders usually diagnosed in childhood or in adolescence, and paternal anxiety disorders. Table 4 depicts the distribution of parental psychiatric disorders diagnosed prior to the birth of the offspring, and their associations to BPD in the offspring, case vs. control. Adjusted analyses demonstrate associations between BPD in offspring and any parental psychiatric diagnosis [OR (maternal) 2.08 (95 % CI 1.13–3.85); OR (paternal) 2.47 (95 % CI 1.52–4.00)], schizophrenia and related psychoses [OR (maternal) 3.53 (95 % CI 1.25–9.93); OR (paternal) 8.45 (95 % CI 2.27–31.46)] and other affective disorders [OR (maternal) 2.83 (95 % CI 1.12–7.12); OR (paternal) 4.31 (95 % CI 1.81–10.23)]. Regarding Tables 2, 3 and 4, two different unadjusted OR’s are reported. The primary unadjusted analysis included all cases and their matched controls. In the secondary unadjusted analysis, cases and matched controls lacking some information on covariates were excluded. This exclusion was similarly applied in the adjusted analyses. Consequently, differences between the adjusted OR’s as compared to the secondary unadjusted OR’s cannot be due to excluded data. Complete covariate data were available for 679 cases and 1,271 matched controls. Lack of information on smoking during pregnancy was the main reason for cases and controls being excluded from these analyses. Finally, we adjusted individually for covariates in analyses of maternal and paternal alcohol and drug addiction/abuse. In no other maternal or paternal category was there a change in the statistical significance between the unadjusted analyses on subjects with complete covariate data and adjusted analyses. We found that no single covariate had an impact strong enough for such a change to occur in the association between parental addiction/abuse category and BPD in offspring (data available on request).

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Discussion The present study shows an association between parental BPD and BPD in the offspring, thereby confirming findings from previous population-based studies [8–14]. Associations were also seen in both maternal and paternal schizophrenia and related psychoses. Previous populationbased studies have consistently shown offspring BPD to be associated with parental schizophrenia and schizoaffective disorder [8–10, 12, 14], even though none of them have reported results for all parental schizophrenic and related psychoses (referring to ICD-10 diagnoses F20–29). These population-based studies along with findings from genetic studies support a familial link between schizophrenia and BPD, which may be of genetic and environmental origin. Genome-wide association studies have found several susceptibility genes common to both disorders, particularly a gene (ZNF804A) coding for a zinc finger binding protein and another (CACNA1C) coding for a protein involved in L-type voltage-dependent calcium channels [30–32]. The notion that schizophrenia and BPD are completely separate entities is further challenged by patients presenting with wide variations of mixed psychotic and affective symptoms. The relation between BPD and schizophrenia may rather be dimensional, with schizoaffective disorder between the extremes of this continuum [33, 34]. Hence, the association we found between the other psychotic disorders subcategory in parents and BPD in the offspring may partly be due to parental disorders relating to and showing traits of BPD, schizoaffective disorder and/or schizophrenia, and yet failing to fulfill the diagnostic criteria for any of these disorders. This may lead to less specific diagnoses, other non-organic psychosis (F28) or unspecified non-organic psychosis (F29), which are included in the other nonaffective psychoses subcategory. A population-based study [8] demonstrated an association between BPD in the offspring and parental affective disorders other than BPD. A recent register-based study [35] reported an increased risk of unipolar depression in siblings of persons with BPD. Our results reinforce findings from previous studies pointing at a simultaneous clustering

Soc Psychiatry Psychiatr Epidemiol Table 3 Frequencies, percentages and OR’s with 95 % CI’s for parental psychiatric diagnoses in bipolar disorder cases and controls by category of disorder Case n (%)

Control n (%)

1,308 (70.3)

3,167 (86.9)

553 (29.7)

476 (13.1)

92 (4.9)

Schizophrenia Schizoaffective disorder

Unadjusted OR (95 % CI)

Unadjusted, subjects with complete covariate data: OR (95 % CI)

Adjusteda OR (95 % CI)

Maternal psychiatric diagnoses Any psychiatric diagnosis No Yes Schizophrenia and related psychosesb

Other nonaffective psychoses

2.79 (2.42–3.22)

3.15 (2.45–4.05)

2.97 (2.29–3.87)

56 (1.5)

3.96 (2.80–5.61)

3.41 (1.87–6.22)

3.14 (1.69–5.84)

37 (2.0)

20 (0.6)

3.71 (2.15–6.41)

2.24 (0.86–5.85)

11 (0.6)

3 (0.1)

8.17 (2.26–29.52) 11.43 (1.34–97.51)

2.19 (0.81–5.94) 11.49 (1.21–108.92)

44 (2.4)

33 (0.9)

2.83 (1.79–4.50)

2.68 (1.21–5.95)

2.40 (1.07–5.41)

72 (3.9)

26 (0.7)

5.86 (3.73–9.21)

5.86 (2.91–11.83)

5.17 (2.52–10.62)

261 (14.0) 26 (1.4)

229 (6.3) 30 (0.8)

2.68 (2.21–3.24) 2.01 (1.16–3.47)

3.03 (2.17–4.24) 2.61 (1.10–6.17)

2.96 (2.08–4.21) 2.63 (1.08–6.42)

76 (4.1)

101 (2.8)

1.85 (1.36–2.53)

2.14 (1.21–3.79)

2.00 (1.11–3.60)

Alcohol and drug addiction/abuse

26 (1.4)

30 (0.8)

2.31 (1.34–4.00)

4.97 (1.20–20.59)

3.73 (0.89–15.66)

Disorders usually diagnosed in childhood or in adolescencec

12 (0.6)

9 (0.3)

2.36 (0.99–5.63)

1.79 (0.57–5.59)

1.28 (0.39–4.19)

2.42 (2.09–2.79)

2.62 (2.06–3.34)

2.60 (2.01–3.36)

Bipolar disorder Other affective disorders Anxiety disorders Other neurotic and personality disorders and other nonpsychotic disorders

Paternal psychiatric diagnoses Any psychiatric diagnosis No Yes Schizophrenia and related psychosesb Schizophrenia

1,318 (72.4)

3,121 (86.7)

503 (27.6)

480 (13.3)

60 (3.3)

41 (1.1)

3.33 (2.22–5.01)

3.85 (1.75–8.49)

4.49 (1.97–10.27)

26 (1.4)

14 (0.4)

3.60 (1.88–6.91)

5.06 (1.34–19.13)

5.01 (1.25–20.13)

Schizoaffective disorder Other nonaffective psychoses

3 (0.2)

4 (0.1)

1.47 (0.32–6.71)

NA

d

NAd

31 (1.7)

23 (0.6)

2.64 (1.54–4.54)

3.08 (1.11–8.52)

3.71 (1.28–10.78)

72 (4.0)

22 (0.6)

7.65 (4.68–12.51)

8.48 (4.05–17.77)

8.07 (3.77–17.26)

185 (10.2) 20 (1.1)

168 (4.7) 31 (0.9)

2.55 (2.04–3.19) 1.35 (0.77–2.39)

2.69 (1.82–3.97) 1.37 (0.53–3.55)

2.96 (1.97–4.47) 1.18 (0.43–3.21)

65 (3.6)

71 (2.0)

2.07 (1.47–2.92)

2.03 (1.20–3.45)

1.93 (1.11–3.35)

Alcohol and drug addiction/abuse

97 (5.3)

141 (3.9)

1.63 (1.24–2.14)

1.77 (1.11–2.83)

1.59 (0.97–2.58)

Disorders usually diagnosed in childhood or in adolescencec

15 (0.8)

13 (0.4)

2.15 (1.02–4.54)

2.43 (0.84–7.05)

2.28 (0.77–6.77)

Bipolar disorder Other affective disorders Anxiety disorders Other neurotic and personality disorders and other nonpsychotic disorders

a

Adjusted for maternal and paternal age, maternal and paternal education, region of birth and maternal smoking during pregnancy

b

The subcategories were analyzed hierarchically within this category. Subjects may belong to only one of the subcategories

c

This category was assessed separately, without hierarchy. Subjects in this category may at the same time belong to another category

d

Not applicable (due to low sample size)

of BPD and other affective disorders between first-degree relatives. In addition, BPD in the offspring was associated with anxiety disorders in mothers. We are not aware of any previous population-based studies on the association between anxiety disorders in parents and BPD in the offspring. However, genetic studies have found anxiety disorders and BPD to share several candidate genes

suggesting genetic overlap between these disorders [36]. Furthermore, children of parents with BPD have an increased risk of developing a wide range of psychopathology, including depressive, substance use, conduct, oppositional defiant and also anxiety disorders [37]. Therefore, our finding calls for further studies attempting to unravel the relation between BPD and anxiety disorders.

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Any parental psychiatric disorder was associated with BPD in the offspring. The OR of BPD in the offspring was 2.79 (95 % CI 1.97–3.94) when only the mother had a psychiatric diagnosis and 2.50 (95 % CI 1.81–3.46) when only the father had a diagnosis. When both parents had a psychiatric diagnosis, the OR increased to 5.36 (95 % CI 3.03–9.46). There may be both genetic and environmental causes for this increase. BPD may have genetic factors in common with psychiatric disorders even beyond psychotic and affective disorders. For example, some genetic studies have indicated that BPD has a genetic link to attention deficit hyperactivity disorder and substance use disorders [38–41]. Some of the increase may also be connected to childhood environmental factors. Parental mental illness may have negative effects on family environment and parenting [42–45] and thus influence the child’s early development. These negative effects may then be stronger with both parents being affected. In addition, the associations could partly originate from reverse causation. For instance, it is plausible to speculate that mental problems in a child, by arousing concern in a parent, might predispose to parental psychiatric illness. However, when we examined BPD in the offspring in relation to any maternal or paternal psychiatric disorder diagnosed before the birth of the child, the associations in the unadjusted as well as the adjusted analyses remained statistically significant in both mothers and fathers. We continued by examining the different categories of parental psychiatric disorders diagnosed before the birth of the cases and controls (Table 4). Despite the smaller sample sizes, the associations to BPD in offspring reached statistical significance in the adjusted analyses in two maternal and paternal diagnostic categories: schizophrenia and related psychoses, and other affective disorders. The findings could to some extent be explained by a genetic link between BPD and these disorders. On the other hand, some of the parents diagnosed with other affective disorders before the birth of cases and controls may have had BPD which was initially misdiagnosed as unipolar depression. This might explain why there were so few parents diagnosed with BPD prior to the birth of the offspring, potentially leading to non-significant findings. The results of the bivariate tests (Table 1) indicate that all the included covariates have some impact on the associations found between parental psychiatric disorders and BPD in the offspring. On the other hand, the impact of adjustment with covariates was rarely strong enough for the statistical significance to change between the unadjusted analyses including subjects with complete covariate data and the adjusted analyses (Table 3). Among the seven diagnostic categories, this only occurred for maternal and paternal alcohol and drug addiction/abuse. Although these diagnoses were significantly associated with BPD in the

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offspring in the unadjusted analyses, they were no longer significant in the adjusted analyses. When we examined the association between parental alcohol and drug addiction/ abuse and BPD in offspring adjusting for only one covariate at a time, the associations remained statistically significant for all six analyses. Apparently the association between parental alcohol and drug addiction/abuse and BPD in offspring may lose its statistical significance in the adjusted analyses due to additive effects of some covariates. Since the primary unadjusted analysis, in contrast to the adjusted analysis, included all cases and controls, regardless of whether all covariate data were available or not, the differences in the two samples of subjects might have influenced the results of the adjusted analysis. However, when the primary unadjusted analysis was compared to the secondary unadjusted analysis including only subjects with complete covariate data, the results were quite similar (the most relevant difference being that the association to paternal disorders usually diagnosed in childhood or in adolescence became non-significant in the secondary analysis). Therefore, we estimate the impact of missing data on the adjusted results to be small. There are limitations in this study to be considered. First, the BPD cases in our study sample are restricted to persons whose BPD has been recognized and diagnosed and that have utilized public specialized mental health services. Some proportion of the BPD cases in Finland will be missed since persons with less severe BPD may not utilize specialized mental health services and in that case will not be found in the nationwide registers. However, the healthcare services in Finland are financed by public means so access to health care, including specialized services, is not dependent on income. Second, outpatient treatment in private clinics is not recorded in the register. Even then, cases will be missed only if they have never received any inpatient treatment for BPD since all inpatient units in Finland are public and the register has complete coverage of inpatient treatments. Third, diagnostic validity may be negatively affected by the fact that cases, controls and parents were not directly ascertained and the diagnoses are clinical, and not systematically based on standardized interviews. However, the validity of the FHDR has been shown to be good for mental disorder diagnoses in general [46] and for BPD I in particular [47, 48]. Fourth, the sample only includes BPD cases aged 25 years and below. The previous population-based studies had higher maximum age limits, ranging between 28 years [11] and 72 years [10]. There are studies indicating that the genetic contribution may be larger in early-onset BPD compared to later-onset BPD [49]. It is therefore possible that there is some bias in our sample towards BPD with heritability above the average. Fifth, while information on smoking

Soc Psychiatry Psychiatr Epidemiol Table 4 Frequencies, percentages and OR’s with 95 % CI’s for parental psychiatric diagnoses given BEFORE the birth of bipolar disorder cases and controls by category of disorder Case n (%)

Control n (%)

1,797 (96.6)

3,584 (98.4)

Unadjusted OR (95 % CI)

Unadjusted, subjects with complete covariate data: OR (95 % CI)

Adjusteda OR (95 % CI)

2.14 (1.50–3.07)

2.26 (1.25–4.08)

2.08 (1.13–3.85)

Maternal psychiatric diagnoses Any psychiatric diagnosis No Yes

64 (3.4)

59 (1.6)

34 (1.8)

13 (0.4)

5.19 (2.74–9.86)

3.44 (1.26–9.40)

3.53 (1.25–9.93)

8 (0.4)

5 (0.1)

3.20 (1.05–9.78)

1.84 (0.46–7.41)

1.82 (0.43–7.75)

24 (1.3)

26 (0.7)

1.94 (1.11–3.40)

3.03 (1.23–7.46)

2.83 (1.12–7.12)

5 (0.3)

4 (0.1)

2.33 (0.62–8.72)

4.00 (0.36–44.11)

3.86 (0.34–43.40)

Other neurotic and personality disorders and other nonpsychotic disorders

18 (1.0)

17 (0.5)

2.10 (1.08–4.08)

1.54 (0.51–4.62)

1.24 (0.39–3.90)

Alcohol and drug addiction/abuse

3 (0.2)

3 (0.1)

2.00 (0.40–9.91)

Disorders usually diagnosed in childhood or in adolescenceb

3 (0.2)

4 (0.1)

1.23 (0.27–5.57)

2.00 (0.28–14.20)

1.43 (0.20–10.33)

2.12 (1.58–2.86)

2.58 (1.63–4.11)

2.47 (1.52–4.00)

2.93 (1.55–5.53)

7.60 (2.13–27.09)

8.45 (2.27–31.46)

4.20 (1.59–11.07) 9.10 (1.06–78.44)

8.14 (0.91–72.81)

Schizophrenia and related psychoses Bipolar disorder Other affective disorders Anxiety disorders

NAc

NAc

Paternal psychiatric diagnoses Any psychiatric diagnosis No

1,724 (94.7)

Yes

3,509 (97.5)

97 (5.3)

92 (2.6)

Schizophrenia and related psychoses

24 (1.3)

16 (0.4)

Bipolar disorder

13 (0.7)

6 (0.2)

Other affective disorders

35 (1.9)

27 (0.8)

2.71 (1.63–4.51)

4.41 (1.90–10.22)

4.31 (1.81–10.23)

Anxiety disorders

10 (0.6)

15 (0.4)

1.25 (0.56–2.80)

0.92 (0.23–3.71)

0.75 (0.17–3.24)

Other neurotic and personality disorders and other nonpsychotic disorders Alcohol and drug addiction/abuse

23 (1.3)

31 (0.9)

1.53 (0.88–2.63)

1.77 (0.76–4.12)

1.60 (0.66–3.86)

15 (0.8)

14 (0.4)

2.14 (1.03–4.46)

1.05 (0.35–3.16)

0.92 (0.29–2.92)

5 (0.3)

6 (0.2)

1.67 (0.51–5.46)

8.00 (0.89–71.58)

6.23 (0.68–57.38)

Disorders usually diagnosed in childhood or in adolescenceb a

Adjusted for maternal and paternal age, maternal and paternal education, region of birth and maternal smoking during pregnancy

b

This category was assessed separately, without hierarchy. Subjects in this category may at the same time belong to another category

c

Not applicable (due to low sample size)

during pregnancy did not cover the years 1983–1986, the exposure was recorded during pregnancy, thus limiting any recall bias. Sixth, parental education reflected their educational status at the end of 1995, not at the time of birth of the offspring. Seventh, we cannot rule out that the effects of some confounders could be related to certain familial factors that were not available in the database. In conclusion, we have confirmed our hypothesis that BPD in the offspring is related to parental affective disorders and schizophrenia and related psychoses. Contrary to our expectation, we also observed that BPD in offspring was related to most of the other parental psychiatric disorders examined. Adjustments with the selected covariates had only a minor impact on the associations. The subanalysis, by being restricted to parental psychiatric

disorders diagnosed prior to birth of the offspring, demonstrates how these associations are influenced by childindependent factors. Acknowledgments The study was supported by grants from NARSAD Independent Investigator Award, USA (Andre Sourander), the Sigrid Juselius Foundation, Finland (Andre Sourander), National Institutes of Health with grant number 5K02-MH65422 (Alan S. Brown), and the Finnish Epilepsy Society (Elina Jokiranta). They had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. We thank the study investigators and staff at medical centers involved in this research. Specifically we would like to thank the members involved in the data collection process including: Jarna Lindroos, Jukka Huttunen, Juha-Pekka Virtanen, Kristiina Saanakorpi, Ulla Kulmala, Tanja Sarlin, Terja Ristkari and Lauri

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Soc Psychiatry Psychiatr Epidemiol Sillanma¨ki from Research Centre for Child Psychiatry, University of Turku. Conflict of interest The authors declare that they have no conflicts of interest.

Appendix See Table 5.

Table 5 Detailed description of psychiatric categories Diagnostic category

Current classification

Previous classifications

ICD-10 (1996–present)

ICD-9 (1987–1995)

ICD-8 (1969–1986)

F20 schizophrenia, F21 schizotypal disorder, F22 delusional disorder, F23 acute and transient psychotic disorders, F24 induced delusional disorder, F25 schizoaffective disorder, F28 other non-organic psychotic disorders, F29 unspecified non-organic psychosis

295, 297, 2989X, 3012C

295, 297, 298.20, 298.30, 298.99, 299

Subcategory Other nonaffective psychoses F21, F22, F23, F24, F28, F29

Other nonaffective psychoses 2954A, 297, 2989X, 3012C

Other nonaffective psychoses 295.40, 295.50, 297, 298.20, 298.30, 298.99, 299

Bipolar disorder

F31

2962A-G, 2963A-G, 2964A-G, 2967A

296.10, 296.30

Other affective disorders

F30 manic episode, F32 depressive episode, F33 recurrent depressive disorder, F34 persistent mood (affective) disorders(incl. cyclothymia and dysthymia), F38 other single mood (affective) disorder, F39 unspecified mood (affective) disorder

2961A-G, 2968A, 3004A, 2988A

296 (excluding 296.10 and 296.30), 298.00, 298.10, 300.41

Anxiety disorders

F40 phobic anxiety disorders F41 other anxiety disorders (excluding F41.2) F42 obsessive– compulsive disorder

3000A, 3000B, 3000C, 3002B, 3002C, 3002D, 3002X, 3003A

300.00, 300.20, 300.30

Other neurotic and personality disorders and other nonpsychotic disorders

F41.2 mixed anxiety and depression, F43 reaction to severe stress and adjustment disorders, F44 dissociative amnesia, F45 somatoform disorders, F48 other neurotic disorders, F50 eating disorders, F51 non-organic sleep disorders, F52 lack or loss of sexual desire, F53 mental and behavioral disorders associated with the puerperium, not elsewhere classified, F54 psychological and behavioral factors associated with disorders or diseases classified elsewhere, F55 abuse of non-dependence producing substances, F59 unspecified behavioral syndromes associated with physiological disturbances, F60 specific personality disorders, F61 mixed and other personality disorders, F62 enduring personality changes, not attributable to brain damage and diseases, F63 habit and impulse disorders, F64 gender identity disorders, F65 fetishism, F66 psychological and behavioral disorders associated with sexual development and orientation, F68 other disorders of adult personality and behavior, F69 unspecified disorder of adult personality and behavior, F99 mental disorder not otherwise specified

300–302 (excluding 3000A, 3000B, 3000C, 3002B, 3002C, 3002D, 3002X, 3003A, 3004A and 3012C), 3071A, 3074A, 3074F, 3074H, 3075A, 3075B, 3075C, 3075E, 3078A, 3079X, 309 (excluding 3092A, 3092B, 3093A and 3094A), 312 (excluding 3120A and 3123D)

300–302, (excluding 300.00, 300.20, 300.30, 300.41), 305, 306.40, 306.50, 306.98, 307.99

Alcohol and drug addiction/abuse

Mental and behavioral disorders due to use of… F10 alcohol, F11 opioids, F12 cannabinoids, F13 sedatives or hypnotics, F14 cocaine, F15 other stimulants, including caffeine, F16 hallucinogens, F17 tobacco, F18 volatile solvents, F19 multiple drug use and use of other psychoactive substances

303–305, 291–292

303–304, 291, 294.30

Schizophrenia and related psychoses

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Soc Psychiatry Psychiatr Epidemiol Table 5 continued Diagnostic category

Disorders usually diagnosed in childhood or in adolescence

Current classification

Previous classifications

ICD-10 (1996–present)

ICD-9 (1987–1995)

ICD-8 (1969–1986)

F70–F79 intellectual disability, F80 specific developmental disorders of speech and language, F81 specific developmental disorders of scholastic skills, F82 specific developmental disorder of motor function, F83 mixed specific developmental disorders, F84.0 childhood autism, F84.1 atypical autism, F84.4 overactive disorder associated with mental retardation and stereotyped movements, F84.5 Asperger’s syndrome, F84.8 other pervasive developmental disorders, F84.9 pervasive developmental disorder, unspecified, F88 other disorders of psychological development, F89 unspecified disorder of psychological development, F90 hyperkinetic disorders, F91 conduct disorders, F92 mixed disorders of conduct and emotions, F93 emotional disorders with onset specific to childhood, F94 disorders of social functioning with onset specific to childhood and adolescence, F95 tic disorders, F98 other behavioral and emotional disorders with onset usually occurring in childhood and adolescence

299, 313–315, 317–319, 3120A, 3123D, 3070A, 3070B, 3072A, 3072B, 3072C, 3072D, 3073A, 3074G, 3075D, 3076A, 3076B, 3076C, 3077A, 3092A, 3092B, 3093A, 3094A

306.00, 306.10, 306.20, 306.30, 306.60, 306.70, 308.99, 310-315

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