Parental Mental Disorders and Ages of Onset of Severe Mental Disorders in Offspring: A Nationwide Family-link Study

doi:10.21203/rs.3.rs-3022036/v1

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Parental Mental Disorders and Ages of Onset of Severe Mental Disorders in Offspring: A Nationwide Family-link Study

https://doi.org/10.21203/rs.3.rs-3022036/v1

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Objective

Few studies have investigated the association between age of onset of severe mental disorders (SMDs) in offspring and the likelihood of diagnoses of parental mental disorder.

Method

We enrolled 212,333 patients with schizophrenia, bipolar disorder (BD), or major depressive disorder (MDD) and 2,123,329 controls matched for age, sex, and demographics from the National Health Insurance Database of Taiwan. Poisson regression models were used to examine the likelihood of diagnoses of five mental disorders in their parents compared to the parents of the controls (reported as odds ratio (OR) with 95% confidence interval), including schizophrenia, BD, MDD, alcohol use disorder (AUD), and substance use disorder (SUD). The study cohort was classified into child-onset, adolescent-onset, and adult-onset groups according to the onset of SMDs in the offspring.

Result

The parents of patients with child-, adolescent-, and adult-onset schizophrenia (OR range: 1.73–9.08, all p < 0.05) or BD (OR range: 1.97–8.17, all p < 0.05) were more likely to be diagnosed with schizophrenia, BD, MDD, AUD, and substance use disorder (SUD) than controls except for AUD in the child-onset group. However, the parents of patients with child-, adolescent-, and adult-onset depressive disorder were more likely to be diagnosed with schizophrenia, BD, MDD, AUD, and SUD (OR range: 1.82–4.76, all p < 0.05) than controls. Sub-analyses stratified by sex showed different patterns of associations between parental mental disorders and offspring mental disorders.

Conclusion

No matter when the SMD occurred during the developmental milestone, their parents had higher likelihood of being diagnosed with schizophrenia, BD, MDD, AUD, and SUD.

Schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD) are severe mental disorders (SMD) that may negatively affect all areas of life including personal, family, and social functioning. Evidence from epidemiological studies has identified a strong association of parental mental disorders with an increased risk of SMD in offspring (Rasic et al., 2014, Gottesman et al., 2010, Dean et al., 2010). Such association might result from multiple interactions across genetic predisposing factors and environmental exposures (Shaffer and Kipp, 2010, Oliver-Parra et al., 2020). Recent studies have found that approximately two-thirds of known genetic factors are commonly shared by schizophrenia, BD, and MDD (Sandstrom et al., 2019, Consortium, 2013). A meta-analysis including 3863 participants reported a 2.5-fold increased risk of SMD in offspring of parents with SMD compared to parents without SMD (Rasic et al., 2014).

To date, only a few population-based studies have addressed the association between offspring SMDs and the likelihood of diagnoses of mental disorders in their parents. A Denmark population-based study in 2010 found elevated risks of a broad range of psychiatric outcomes among offspring with parental histories of mental disorders (Dean et al., 2010). The association of alcohol use disorder (AUD) in offspring with parental SMD and their transmission patterns has also been investigated in several studies, suggesting a shared heritability across AUD and SMD within families(Castillo-Carniglia et al., 2019, Vidal et al., 2012). However, few studies have examined the association of offspring SMD with parental AUD or substance use disorders (SUD), and no studies have specifically investigated the association between age of onset of SMD in offspring and the likelihood of diagnoses of different parental mental disorders. In a family of children with mental disorders, it is important to know the age of onset of such mental disorder and the cross-disorder association in their parents. This information may be helpful for clinicians in the early detection and intervention of SMD in vulnerable populations.

The aims of this study were to examine: (1) the likelihood of mental disorders in the parents of offspring with SMDs; (2) the associations between different ages of onset of SMD in the offspring (i.e., child-onset, adolescent-onset, and adult-onset); and (3) whether fathers and mothers have different patterns of within- and cross-disorder transmission. We hypothesized that offspring SMDs and the age of onset may play an important role in the likelihood of parental mental disorders.

Data acquisition. The Taiwan National Health Research Institute audits and releases the National Health Insurance Research Database (NHIRD) for scientific studies (Huang et al., 2021, Liang et al., 2020). The insurance claim information of the individuals is anonymous to maintain privacy. Comprehensive information on insured individuals is included in the database, including demographic data, clinical visit dates, and disease diagnoses. In this study, using each resident’s unique personal identification number, all the information was linked. Following the method of Chen et al. and Cheng et al, family kinships in the NHIRD were used for genealogy reconstruction (Cheng et al., 2018, Chen et al., 2018b). The diagnostic codes were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many Taiwanese epidemiologic studies (Chen et al., 2018a, Chen et al., 2018b, Chen et al., 2016, Zhang et al., 2021)..

Inclusion criteria of the case and the control groups. Patients with child-onset (< 12 years), adolescent-onset (12-19 years), and adult-onset (20-29 years) SMD were enrolled between January 1 2001 and December 31 2011 as the study cohort. The SMDs were defined as schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM codes: 296 except 296.2x, 296.3x, 296.9x, and 296.82), and depressive disorder (ICD-9-CM codes: 296.2, 296.3, 300.4, and 311). For each study case, we randomly selected 1:10 matched controls based on age, sex, birth time, and residence after eliminating those individuals with any major mental disorder (ICD-9-CM codes: 295, 296, and 300, and 314) in the database. Diagnoses of parental mental disorders, including schizophrenia, BD, depressive disorder, AUD, and SUD were assessed between 2001 and 2011. In addition, to ensure diagnostic validity, the diagnoses of the above mental disorders were given by board-certified psychiatrists at least twice. Income levels (levels 1-3 per month: ≤19,100 NTD (New Taiwanese Dollars), 19,001~42,000 NTD, and > 42,000 NTD) and urbanization levels of residence (levels 1-5, most to least urbanized) were assessed as the proxy for healthcare availability in Taiwan (Liu et al., 2006).

Statistical methods. Chi-squared statistics and F-tests were used to compare categorical and continuous variables, respectively, between study and control cohorts. Some offspring were from the same families, resulting in a clustered study sample (Zou, 2004). After adjustment for demographic data (age, sex, residence, and income), we used Poisson regression models with a robust error variance to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the likelihoods of parental mental disorders, including schizophrenia, BD, depressive disorder, AUD, and SUD, in patients with child-onset, adolescent-onset, and adult-onset SMDs compared with the control group. SAS 9.2 (SAS Institute, Cary, NC, USA) was used for all statistical analyses. All tests were two-tailed, and p < 0.05 was considered statistically significant.

Data availability. As participants did not consent for their data to be publicly shared, even anonymized, data will be made available to only potential collaborators with ethical approval after they submit a research proposal to Bureau of the NHI (https://nhird.nhri.org.tw/).

There were 4259 participants in the child-onset group, 63,227 in the adolescent-onset group, 144,847 in the adult-onset group, and 2,123,329 matched controls (Table 1). We found significant associations between offspring SMD and increased likelihoods of parental psychiatric diagnoses. Parental depressive disorder was the most likely mental disorder in the three groups (child-onset: 12.6%, adolescent-onset: 8.5%, and adult-onset:6.7%). Both the child-onset (2.8%) and adolescent-onset (2.3%) groups had the lowest incidence of parental schizophrenia. In contrast, the lowest incidences of parental disorders were schizophrenia (1.7%) and SUD (1.7%) in the adult-onset group(Figure 1).

The likelihoods (reported as ORs with 95% CIs) of schizophrenia, bipolar disorder, depressive disorder, AUD, and SUD in parents of the three groups compared with controls are shown in Table 2. For schizophrenia, the parents of the child-onset group were more likely to be diagnosed with schizophrenia (OR=9.08, 95%CI: 5.74-14.34), BD (4.63, 2.59-8.27), MDD (1.96, 1.20-3.20), and SUD (2.03, 1.00-4.11) than the controls. The parents of the adolescent-onset schizophrenia group and the adult-onset schizophrenia group were more likely to be diagnosed with schizophrenia (adolescent-onset: 6.60, 6.06-7.20; adult-onset: 5.28, 4.94-5.64), BD (adolescent-onset: 4.04, 3.64-4.47; adult-onset: 3.21, 2.96-3.48), MDD (adolescent-onset: 2.41, 2.24-2.59; adult-onset: 2.21, 2.10-2.33), AUD (adolescent-onset: 1.81 , 1.61-2.03); adult-onset: 1.73, 1.58-1.90), and SUD (adolescent-onset: 2.09, 1.85-2.37, adult-onset: 1.89, 1.70-2.09) than the controls.

For BD (Table 3), the parents of the child-onset group were more likely to be diagnosed with schizophrenia (2.50, 1.38-4.56), BD (9.90, 7.34-13.35), MDD (3.71, 2.83-4.85), and SUD (1.97, 1.21-3.20) than the controls. Parents of the adolescent-onset BD group and the adult-onset BD group had significantly higher likelihood of diagnosis with schizophrenia (adolescent-onset: 3.64, 3.10-4.28; adult-onset: 2.58, 2.28-2.91), BD (adolescent-onset: 8.17, 7.35-9.09; adult-onset: 5.58, 5.14-6.05), MDD (adolescent-onset: 3.32, 3.04-3.63, adult-onset: 2.82, 2.65-2.99), AUD (adolescent: 2.41, 2.09-2.78; adult-onset: 2.47, 2.24-2.72), and SUD (adolescent: 2.74, 2.35-3.20; adult-onset: 2.57, 2.29-2.88).

For depressive disorders (Table 4), the parents of all three groups were more likely to be diagnosed with schizophrenia (child-onset: 3.28, 2.64-4.06; adolescent-onset: 2.21, 2.04-2.38; adult-onset: 1.64 , 1.55-1.74), BD (child-onset: 4.59, 3.87-5.45; adolescent-onset: 3.13, 2.95-3.33, adult-onset: 2.15, 2.04-2.26), MDD (child-onset: 4.76 , 4.31-5.26; adolescent-onset: 3.03, 2.93-3.14); adult-onset: 2.35, 2.29-2.42), AUD (child-onset: 1.82, 1.51-2.21; adolescent-onset: 2.18, 2.07-2.31); adult-onset: 1.89, 1.81-1.98) and SUD (child-onset: 2.69, 2.25-3.21; adolescent-onset: 2.68, 2.53-2.85; adult-onset: 2.23, 2.12-2.34).

The result of sub-analyses stratified by sex was showed in Tables 2, 3 and 4. We found different relationships between SMD patients and the likelihood of paternal/maternal disorders for the male and female offspring. The mothers of the child-onset schizophrenia group had the highest likelihood (13.49, 7.72-23.57) of being diagnosed with schizophrenia. The mothers of the child-onset BD group had the highest likelihood (12.51, 7.16-21.83) of being diagnosed with BD. As for the likelihood of parental MDD, AUD, and SUD, the group that had the highest likelihood were mothers of the child-onset MDD group (4.90, 4.20-5.70), adolescent-onset BD group (2.56, 2.11-3.10), and child-onset schizophrenia group (3.17, 1.40-7.20). The fathers of the child-onset schizophrenia group had the lowest likelihood of being diagnosed with SUD (0.98, 0.24-3.97).

To the best of our knowledge, our study is the largest investigation of the association between parental mental disorders and offspring with SMDs at different onset stages. Our findings were as follows: (1) the parents of offspring with SMDs had higher likelihoods of being diagnosed with common mental disorders; (2) both within-disorder and cross-disorder transmissions were observed, though within-disorder transmission appeared to be more evident; and (3) parents of the child-onset SMD group appeared to have the highest likelihood of being diagnosed with all five mental disorders, followed by the adolescent-onset SMD group and adult-onset SMD group.

Offspring with schizophrenia:

We found that parents of the child-onset schizophrenia group had the highest likelihood of being diagnosed with schizophrenia, and they also had higher likelihoods of being diagnosed with BD, MDD, AUD, or SUD compared to parents of the matched controls. These findings are consistent with those of familial risk studies (Rasic et al., 2014, Dean et al., 2010, Lichtenstein et al., 2009). A meta-analysis has provided evidence of within-disorder transmission for schizophrenia (Rasic et al., 2014). Genetic-environmental correlations may play an important role in the within-disorder transmission of schizophrenia (Wahbeh and Avramopoulos, 2021). Moreover, previous studies have reported polymorphisms of brain-derived neurotrophic factor genes, catechol-O-methyltransferase genes, and their interaction with childhood abuse that increased risks of adult psychosis (Alemany et al., 2011, Alemany et al., 2014). There is also strong association between schizophrenia and MicroRNAs which are an important genetic marker that influences regulation of neural development (Mahmoudi and Cairns, 2017).

We found that parents of the child-onset schizophrenia group had the highest likelihood of being diagnosed with not only schizophrenia but also BD. Most population-based studies have demonstrated that offspring of parents with mental disorders had earlier likelihood of being diagnosed with mental disorders than those of parents without mental disorders (Gottesman et al., 2010, Dean et al., 2010). Importantly, our study suggests higher likelihood of cross-disorder transmission between schizophrenia and BD. Previous large-scale genome-wide association studies (GWASs) have provided strong evidence showing partial overlap of genetic influences in these two disorders (Cardno and Owen, 2014, Sandstrom et al., 2019). A large sample GWAS involving 50,000 participants also revealed genome-wide significant associations of three loci, CACNA1C, ANK3, and ITIH3-ITIH4 in the combined sample of schizophrenia and BD (Finseth et al., 2014).

Offspring with BD

We found that the child-onset BD group had the highest likelihood of parental BD. Previous studies have demonstrated within family transmission patterns between different mood disorders(Rasic et al., 2014, Mortensen et al., 2003, Gottesman et al., 2010). A nation-wide cohort study (2.1 million individuals) in Denmark identified a near 13-fold increased risk in people who had first degree relatives diagnosed with bipolar affective disorders (Mortensen et al., 2003). A meta-analysis has reported a 6.42-fold increased risk of BD in offspring of parents with BD compared with controls (Rasic et al., 2014). Our study extends these previous study findings; such likelihood is even higher in the child-onset BD group (Rasic et al., 2014), suggesting that the child-onset BD group may be more vulnerable to neurodevelopmental dysfunction through within-disorder transmission (Sandstrom et al., 2019). Previous neuroimaging studies have reported deviation of brain structure among BD patients, including thinner cortex, increased volume, and surface of the right inferior frontal gyrus (Hanford et al., 2016, Roberts et al., 2017, Drobinin et al., 2019). One longitudinal neuroimaging study found greater anterior cingulate cortex activity and connection with amygdala while processing emotional regulation tasks in offspring of parents with BD; this study provides some evidence for the association of BD in families with deficits of neurodevelopment (Acuff et al., 2018).

In our study we also found that the likelihood of diagnoses of parental BD and MDD was highest in the child-onset BD group, followed by the adolescent-onset and the adult-onset groups. The increased likelihood of BD and MDD may be related to several factors. The core and specific symptoms of mood instability and irritability, which also cause interpersonal interaction problems among families, have been identified as a predictor of familial mood disorders (Hafeman et al., 2016, Rice et al., 2017). Common environmental factors that may contribute to family transmission such as family conflicts, frequent stressful life events, and poor socioeconomic status, are shared by affective disorders (Kemner et al., 2015, Ferreira et al., 2013).

Offspring with depressive disorders

We suggested that the earlier-onset depressive disorder group is associated with high likelihood of parental common mental disorders. The likelihood of diagnoses of parental schizophrenia, BD, MDD and SUD was highest in the child-onset group, followed by the adolescent-onset group and then the adult-onset group. The findings in our depressive disorder group were consistent with previous studies(Rasic et al., 2014, Lieb et al., 2002). A previous meta-analysis found significant associations between MDD and several common mental disorders such as schizophrenia, BD, MDD, and SUD in the direct bloodline (Rasic et al., 2014). A prospective-longitudinal study investigating 2427 offspring and their parents for MDD associations, found that parental MDD increased the risk of offspring MDD and simultaneously influenced the onset age (Lieb et al., 2002). In addition, early age of onset, high severity of symptoms, persistent and more depressed episodes, and poor social contact were reported in MDD patients who had depressed parents (Lieb et al., 2002). The inheritability of MDD is the interaction of several biological and environmental factors (Uher, 2014, Lopizzo et al., 2015). Four possible transmission mechanisms have been proposed: (i) genetic heritability; (ii) child neuroregulatory mechanisms dysfunction; (iii) child exposure to maternal negative patterns, and (iv) stressful circumstances in a child’s life (Goodman and Gotlib, 1999). Recent studies have found that heritability of MDD is influenced by small contributions of several genes but without pronounced effects of principal genes (Shadrina et al., 2018). The concept of Adverse Child Experiences was proposed in research surveying the relationship between childhood abuse and household dysfunction, which may be caused by depression, substance abuse by parents, and the child’s mental health.(Felitti et al., 1998). Mentally ill parents can lead to negative experiences such as childhood neglect, multiple life stresses, and low socioeconomic status that may affect the neurodevelopment of the child, and eventually increase the risk of depression (Agerup et al., 2015, Halonen et al., 2022).

A strength of our study is that we recruited a large sample size of nearly 2 million participants; this minimized selection bias and means that the result can be generalizable to other Asian populations. Also, because of the accessibility and inexpensiveness of Taiwan's National Health Insurance, most of the patients with mental problems could be surveyed and recruited regardless of the socioeconomic status of the family. The third strength of our studies was that this is the first study to examine the association of offspring disorders and their onset age with the possibility of their parents to have mental disorders. Importantly, we recruited and assessed a subgroup of child-onset patients (onset age <12 years), which was different from previous nationwide population-based studies (Gottesman et al., 2010, Dean et al., 2010). The sample size of child-onset patients was large (4259), and was representative. Our findings in child-onset patients may be seen as a foundation for further research in familial risk and onset age.

The delayed diagnosis of SMD causes severe consequences such as higher suicide and violence risks, more medical and social comorbidities, and inappropriate and insufficient treatment (Judd et al., 2005). As a result, the onset ages of SMD offspring represent critical information for prevention strategies and early intervention in clinical, and family-focused therapy (Brent et al., 2015, Miklowitz et al., 2013). Integrating our findings and those of other studies, we suggest that there is a transgenerational transmission of either within or cross disorders which has an impact on family members of different onset ages of SMD patients. The associations are strongest among concordance disorders, and complex transmission is found in cross-disorders of other common mental disorders. Further studies exploring the shared risk factor of mental disorders in the family should focus on cross-disorder approaches. We conclude that onset ages of SMD in offspring are strong predictors of parental disorders. This highlights the importance of inclusion of family members when deciding the individual’s treatment strategy.

Limitations

Our study had several limitations. First, the prevalence of schizophrenia, BD, MDD, AUD, SUD may have been underestimated. We could include only those who visited the medical department and received treatment at least thrice within 1 year. Second, we followed up the individuals for only 10 years, hence any late onset mental disorders might not have been assessed. Finally, some psychosocial factors were not available in the NHIRD. For instance, Hyland and colleagues have reported influences of family dissociations, advanced parental ages, childhood adversity on the risk of child and early adult onset mood disorders (Hyland et al., 2016). In addition, the NHIRD did not contain any information regarding medical exposures of parents, substance/alcohol/cigarette exposures, immigrant status, and education level. Therefore, the interaction effects of these factors and familial risk of severe mental disorders warrant further investigation.

Early onset SMD patients have a high likelihood of having parents with common mental disorders. The likelihood is highest among the same SMD patients and parents. Psychiatrists should take this into account when treating patients with high familial risks and offer prevention strategies including social support.

Conflict of Interest: No conflict of interest.

Funding Source: The study was supported by grant from Taipei Veterans General Hospital (V106B-020, V107B-010, V107C-181, V108B-012, V110C-025, V110B-002), Yen Tjing Ling Medical Foundation (CI-109-21, CI-109-22, CI-110-30) and Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3, 108-2314-B-075 -037). The funding source had no role in any process of our study.

Financial Disclosure: All authors have no financial relationships relevant to this article to disclose.

Ethical approval.

This study protocol was reviewed and accepted by an Institutional Review Board of Taipei Veterans General Hospital (2018-07-016AC) and waived the requirement for informed consent because de-identified data were used in this study and no participants were actively enrolled.

Declaration of generative AI in scientific writing.

All authors declare that this paper writing was not generated or assisted by AI.

Competing interest.

The authors have no relevant financial or non-financial interests to disclose.

Author contribution statement.

Author Contributions: M.H.C. and C.S.L. designed the study, wrote the protocol. C.S.L. and P.Y.C drafted the manuscript. M.H.C. and T.W.H. analyzed the data. C.M.C., T.W.H., Y.M.B., T.P.S.and S.J.T. assisted with the preparation and proof-reading of the manuscript. Dr M.H.C. provided the advice on statistical analysis. C.S.L. supervised this program. All authors agreed the submission and publication of this paper.

Availability of data and materials.

The NHIRD was released and audited by the Department of Health and Bureau of the NHI Program for the purpose of scientific research (https://www.apre.mohw.gov.tw/). The NHIRD can be accessed through a formal application that is regulated by the Health and Welfare Data Science Center of Ministry of Health and Welfare, Taiwan.

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Table 1. Demographic characteristics and prevalence of parental mental disorders between patients and controls

	Child-onset group (n = 4259)	Adolescent-onset group (n = 63,227)	Adult-onset group (n = 144,847)	Control group (n = 2,123,329)	p-value
Age in 2011 (years, SD)	15.23 (3.57)	22.90 (4.03)	30.49 (3.93)	27.92 (5.55)	<0.001
Male (n, %)	2582 (60.6)	28,515 (45.1)	65,583 (45.3)	966,800 (45.5)	<0.001
Age at diagnosis (years, SD)	9.74 (1.59)	17.09 (2.09)	24.33 (2.57)		<0.001
Diagnoses of major mental disorders (n, %)
Schizophrenia	286 (6.7)	11,919 (18.9)	25,999 (17.9)
Bipolar disorder	553 (13.0)	5751 (9.1)	14,953 (10.3)
Depressive disorder	3420 (80.3)	45,557 (72.0)	103,895 (71.8)
Diagnoses of parental mental disorders (n, %)
Schizophrenia	119 (2.8)	1470 (2.3)	2482 (1.7)	15,126 (0.7)	<0.001
Bipolar disorder	204 (4.8)	1972 (3.1)	2948 (2.0)	16,808 (0.8)	<0.001
Depressive disorder	536 (12.6)	5357 (8.5)	9769 (6.7)	63,325 (3.0)	<0.001
Alcohol use disorder	135 (3.2)	1922 (3.0)	3149 (2.2)	26,372 (1.2)	<0.001
Substance use disorder	154 (3.6)	1707 (2.7)	2479 (1.7)	18,601 (0.9)	<0.001
Level of urbanization (n, %)					<0.001
1 (most urbanized)	632 (14.8)	13,916 (22.1)	41,456 (28.6)	560,040 (26.4)
2	1346 (31.6)	19,679 (31.1)	47,914 (33.1)	689,390 (32.5)
3	475 (11.2)	7101 (11.2)	20,378 (14.1)	279,550 (13.2)
4	320 (7.5)	6012 (9.5)	14,489 (10.0)	208,210 (9.8)
5 (most rural)	1485 (34.9)	16,519 (26.1)	20,610 (14.2)	386,140 (18.1)
Income-related insured amount (n, %)					<0.001
≤ 19100 NTD/month	860 (20.2)	11,530 (18.2)	25,870 (17.9)	346,571 (16.3)
19001~42000 NTD/month	1702 (40.0)	22,767 (36.0)	49,581 (34.2)	750,347 (35.3)
> 42000 NTD/month	1697 (39.8)	28,930 (45.8)	69,396 (47.9)	1,026,412 (48.4)

SD: standard deviation; NTD: new Taiwan dollar.

Table 2. Risks of parental mental disorders between patients with child-onset vs. adolescent-onset vs. adult-onset schizophrenia and control group#

	Risks of parental mental disorders (OR, 95% CI)
Patients with schizophrenia	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	9.08 (5.74-14.34)	4.63 (2.59-8.27)	1.96 (1.20-3.20)	1.38 (0.65-2.92)	2.03 (1.00-4.11)
Adolescent-onset group	6.60 (6.06-7.20)	4.04 (3.64-4.47)	2.41 (2.24-2.59)	1.81 (1.61-2.03)	2.09 (1.85-2.37)
Adult-onset group	5.28 (4.94-5.64)	3.21 (2.96-3.48)	2.21 (2.10-2.33)	1.73 (1.58-1.90)	1.89 (1.70-2.09)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Male patients with schizophrenia	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	5.16 (2.27-11.71)	4.45 (1.96-10.09)	1.75 (0.86-3.54)	1.51 (0.56-4.09)	0.98 (0.24-3.97)
Adolescent-onset group	6.50 (5.78-7.31)	4.26 (3.72-4.88)	2.42 (2.60-2.67)	1.95 (1.67-2.27)	2.17 (1.86-2.60)
Adult-onset group	5.22 (4.79-5.68)	3.27 (2.94-3.63)	2.34 (2.20-2.50)	1.92 (1.72-2.15)	2.06 (1.82-2.34)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Female patients with schizophrenia	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	13.49 (7.72-23.57)	4.81 (2.12-10.93)	2.19 (1.11-4.30)	1.23 (0.39-3.85)	3.17 (1.40-7.20)
Adolescent-onset group	6.72 (5.92-7.62)	3.78 (3.23-4.41)	2.39 (2.15-2.66)	1.65 (1.38-1.97)	1.98 (1.64-2.39)
Adult-onset group	5.39 (4.86-5.97)	3.15 (2.76-3.59)	2.01 (1.84-2.19)	1.42 (1.24-1.70)	1.59 (1.32-1.91)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)

OR: odds ratio; CI: confidence interval.

#: adjusting for demographic characteristics.

Table 3. Risks of parental mental disorders between patients with child-onset vs. adolescent-onset vs. adult-onset bipolar disorder and control group#

	Risks of parental mental disorders (OR, 95% CI)
Patients with bipolar disorder	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	2.50 (1.38-4.56)	9.90 (7.34-13.35)	3.71 (2.83-4.85)	1.50 (0.91-2.48)	1.97 (1.21-3.20)
Adolescent-onset group	3.64 (3.10-4.28)	8.17 (7.35-9.09)	3.32 (3.04-3.63)	2.41 (2.09-2.78)	2.74 (2.35-3.20)
Adult-onset group	2.58 (2.28-2.91)	5.58 (5.14-6.05)	2.82 (2.65-2.99)	2.47 (2.24-2.72)	2.57 (2.29-2.88)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Male patients with bipolar disorder	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	2.63 (1.32-5.12)	9.07 (6.35-12.95)	3.69 (2.71-5.02)	1.32 (0.72-2.40)	1.82 (1.02-3.24)
Adolescent-onset group	3.37 (2.65-4.30)	7.78 (6.64-9.11)	3.21 (2.82-3.66)	2.24 (1.81-2.78)	2.37-1.86-3.01
Adult-onset group	2.68 (2.25-3.19)	5.63 (5.02-6.37)	2.83 (2.59-3.08)	2.47 (2.14-2.85)	2.56 (2.17-3.01)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Female patients with bipolar disorder	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	1.95 (0.48-7.92)	12.51 (7.16-21.83)	3.72 (2.14-6.48)	2.10 (0.86-5.13)	2.61 (1.06-6.38)
Adolescent-onset group	3.88 (3.13-4.83)	8.52 (7.38-9.84)	3.42 (3.03-3.86)	2.56 (2.11-3.10)	3.07 (2.51-3.76)
Adult-onset group	2.49 (2.10-2.95)	5.51 (4.93-6.17)	2.81 (2.59-3.06)	2.47 (2.16-2.82)	2.57 (2.20-3.01)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)

OR: odds ratio; CI: confidence interval.

#: adjusting for demographic characteristics.

Table 4. Risks of parental mental disorders between patients with child-onset vs. adolescent-onset vs. adult-onset depressive disorder and control group#

	Risks of parental mental disorders (OR, 95% CI)
Patients with depressive disorder	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	3.28 (2.64-4.06)	4.59 (3.87-5.45)	4.76 (4.31-5.26)	1.82 (1.51-2.21)	2.69 (2.25-3.21)
Adolescent-onset group	2.21 (2.04-2.38)	2.13 (2.95-3.33)	3.03 (2.93-3.14)	2.18 (2.07-2.31)	2.68 (2.53-2.85)
Adult-onset group	1.64 (1.55-1.74)	2.15 (2.04-2.26)	2.35 (2.29-2.42)	1.89 (1.81-1.98)	2.23 (2.12-2.34)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Male patients with depressive disorder	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	2.99 (2.23-4.01)	4.47 (3.56-5.61)	4.67 (4.09-5.33)	2.00 (1.58-2.54)	2.68 (2.11-3.39)
Adolescent-onset group	2.23 (1.99-2.51)	3.36 (3.07-3.68)	3.06 (2.91-3.23)	2.28 (2.10-2.48)	2.73 (2.50-2.99)
Adult-onset group	1.79 (1.63-1.96)	2.26 (2.09-2.45)	2.37 (2.27-2.46)	1.85 (1.73-1.99)	2.21 (2.05-2.39)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Female patients with depressive disorder	Schizophrenia	Bipolar disorder	Depressive disorder	Alcohol use disorder	Substance use disorder
Child-onset group	3.68 (2.68-5.04)	4.76 (3.68-6.17)	4.90 (4.20-5.70)	1.56 (1.14-2.14)	2.73 (2.08-3.58)
Adolescent-onset group	2.19 (1.98-2.42)	2.97 (2.74-3.22)	3.01 (2.88-3.15)	2.12 (1.97-2.27)	2.64 (2.45-2.86)
Adult-onset group	1.54 (1.42-1.67)	2.07 (1.94-2.21)	2.35 (2.27-2.43)	1.91 (1.81-2.02)	2.24 (2.10-2.39)
Control group	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)

OR: odds ratio; CI: confidence interval.

#: adjusting for demographic characteristics.

No competing interests reported.

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Parental Mental Disorders and Ages of Onset of Severe Mental Disorders in Offspring: A Nationwide Family-link Study

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