Bipolar disorder is a recurrent chronic severe mental disorder characterized by alternative episodes of mania/hypomania and depression. It affects more than 2% of the world's population regardless of nationality, ethnic origin, or socioeconomic status. Bipolar disorder is one of the main causes of disability, particularly among young people. Bipolar disorder accounts for approximately 7% of disability-adjusted life years caused by mental and substance use disorders. Bipolar disorder leads to cognitive and functional impairment and increased mortality, in particularly through suicide (Muller-Oerlinghausen et al., Reference Muller-Oerlinghausen, Berghofer and Bauer2002; Grande et al., Reference Grande, Berk, Birmaher and Vieta2016; Blanco et al., Reference Blanco, Compton, Saha, Goldstein, Ruan, Huang and Grant2017).
Bipolar disorder is a highly heritable mental illness that transmits intergeneratively and is commonly clustered within families. Lin et al. evaluated a total of 211 families with 1856 individuals who were ascertained through patients with bipolar disorder and showed that individuals from a family with a bipolar proband were more likely to develop bipolar disorder than others [odds ratio (OR) 4.53, 95% confidence interval (CI) 3.09–6.64] (Lin et al., Reference Lin, McInnis, Potash, Willour, MacKinnon, DePaulo and Zandi2006). Song et al., found that the relative risks (RRs) for first-degree relatives (FDRs) of bipolar patients were 5.8–7.9 across different kinships (parents, offspring, and siblings) (Song et al., Reference Song, Bergen, Kuja-Halkola, Larsson, Landen and Lichtenstein2015). They further demonstrated that the siblings of individuals with bipolar disorder had higher risks of schizophrenia (RR 2.8, 95% CI 2.5–3.0), major depressive disorder (MDD, RR 2.1, 95% CI 2.0–2.2), attention deficit hyperactivity disorder (ADHD, RR 2.4, 95% CI 2.1–2.7), and autism spectrum disorder (ASD, RR 2.6, 95% CI 2.3–3.0) (Song et al., Reference Song, Bergen, Kuja-Halkola, Larsson, Landen and Lichtenstein2015). Axelson et al. followed the offspring, aged 6–18 years, of parents with bipolar disorder and the age-, sex-, and neighborhood-matched offspring of community parents without bipolar disorder. They revealed that compared with community offspring, the offspring of parents with bipolar disorder had significantly higher rates of manic/mixed/hypomanic episodes (9.2% v. 0.8%, p < 0.001) and MDD (32.0% v. 14.9%, p < 0.001), and they also had a higher rate of ADHD (30.7% v. 18.1%, p = 0.01) (Axelson et al., Reference Axelson, Goldstein, Goldstein, Monk, Yu, Hickey, Sakolsky, Diler, Hafeman, Merranko, Iyengar, Brent, Kupfer and Birmaher2015). A 12-year follow-up study revealed that 72% of the bipolar offspring developed a lifetime DSM-IV axis I disorder, 54% an affective disorder, and 13% bipolar spectrum disorder (Mesman et al., Reference Mesman, Nolen, Reichart, Wals and Hillegers2013). A meta-analysis of 33 studies with 3863 offspring of parents with severe mental illness (schizophrenia, bipolar disorder or MDD) and 3158 control offspring, and found that offspring of parents with severe mental illness were at increased risk for a range of psychiatric disorders (schizophrenia, bipolar disorder, depression, anxiety, substance use disorder, ADHD) and one third of them may develop a severe mental illness by early adulthood (Rasic et al., Reference Rasic, Hajek, Alda and Uher2014).
However, several previous epidemiological studies failed to find the cross-transmission of bipolar disorder with other psychiatric disorders, including schizophrenia and MDD (Maier et al., Reference Maier, Lichtermann, Minges, Hallmayer, Heun, Benkert and Levinson1993; McGuffin et al., Reference McGuffin, Rijsdijk, Andrew, Sham, Katz and Cardno2003; Merikangas et al., Reference Merikangas, Cui, Kattan, Carlson, Youngstrom and Angst2012; Merikangas et al., Reference Merikangas, Cui, Heaton, Nakamura, Roca, Ding, Qin, Guo, Shugart, Zarate and Angst2014; Vandeleur et al., Reference Vandeleur, Merikangas, Strippoli, Castelao and Preisig2014). Vandeleur et al analyzed a sample of 293 patients with schizophrenia, bipolar disorder or MDD, 110 controls, and 1734 adult FDRs. Among them, probands with schizophrenia, bipolar disorder or MDD and controls did not differ in age and sex; relatives of probands with schizophrenia, bipolar disorder or MDD and controls also did not differ in age and sex. They determined no evidence for cross-transmission of mania and major depressive episodes (OR 0.7, CI 0.5–1.1) and psychosis and mania (OR 1.0, CI 0.4–2.7) (Vandeleur et al., Reference Vandeleur, Merikangas, Strippoli, Castelao and Preisig2014). Maier et al. supported an independent transmission of schizophrenia and bipolar disorder (Maier et al., Reference Maier, Lichtermann, Minges, Hallmayer, Heun, Benkert and Levinson1993). Merikangas et al. further suggested no significant cross-aggregation between affective disorder subtypes suggesting that the familial transmission of manic and major depressive episodes was independent (Merikangas et al., Reference Merikangas, Cui, Heaton, Nakamura, Roca, Ding, Qin, Guo, Shugart, Zarate and Angst2014). A twin study analyzed the data from 30 monozygotic and 37 dizygotic twin pairs in which the proband had bipolar disorder and 68 monozygotic and 109 dizygotic twin pairs in which the proband had MDD and found that approximately 71% of the genetic variance for mania was not shared with depression (McGuffin et al., Reference McGuffin, Rijsdijk, Andrew, Sham, Katz and Cardno2003). Whether bipolar disorder would be co-aggregated with other psychiatric disorders, such as schizophrenia and MDD, required further investigation.
From the genetic view of co-aggregation of major psychiatric disorders, a genome-wide association study (GWAS), which was composed of 33 332 patients and 27 888 controls of European ancestry, reported that five major psychiatric disorders – namely schizophrenia, bipolar disorder, MDD, ASD, and ADHD – may share common genes (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013b). Cross-Disorder Group of the Psychiatric Genomics Consortium further reported that the genetic correlation calculated using common single-nucleotide polymorphisms (SNPs) was high between schizophrenia and bipolar disorder [0.68 ± 0.04 standard error (s.e.), p < 10−16] and moderate between bipolar disorder and MDD (0.47 ± 0.06 s.e., p = 1.5 × 10−14) (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013a). However, the aforementioned studies have only been conducted in the Caucasian population, and most of them focused on the offspring and siblings of bipolar patients; it is difficult to generalize these findings to other ethnicities, such as Asians, and to other kinships, such as parents of bipolar disorder patients.
In our study, using the Taiwan National Health Insurance Research Database (NHIRD), which contains the claims data of the entire Taiwan population (n > 2 300 000), we investigated the risks of schizophrenia, bipolar disorder, MDD, ADHD, and ASD among the FDRs of patients with bipolar disorder, including their parents, offspring, siblings, and twins. We hypothesized that the FDRs of patients with bipolar disorder are more likely to have the aforementioned five major psychiatric disorders than those without bipolar patients, and we also hypothesized that a dose-dependent relationship exists between the risks of the five major psychiatric disorders and the numbers of bipolar patients in a family.
Methods
Data source
Taiwan's National Health Insurance (NHI), a mandatory universal health insurance program, was implemented in 1995 and offers comprehensive medical care coverage to all Taiwanese residents. The National Health Research Institute (NHRI) is in charge of the entire insurance claims database, namely the NHIRD, which consists of healthcare data from >99% of the entire Taiwan population. The NHRI audits and releases the NHIRD for scientific and study purposes. Claims data of subjects included in the NHIRD are anonymous to maintain individual privacy. Comprehensive information on insured subjects is included in the database, including demographic data, dates of clinical visits, and disease diagnoses. Using a unique personal identification number assigned to each resident in Taiwan, all of the information were linked together. Following Kuo et al.’s and Cheng et al.’s method, the recorded family kinships in the NHIRD were used for genealogy reconstruction (Kuo et al., Reference Kuo, Grainge, Valdes, See, Luo, Yu, Zhang and Doherty2015; Cheng et al., Reference Cheng, Chang, Chen, Tsai, Su, Li, Tsai, Hsu, Huang, Lin, Chen and Bai2018). The diagnostic codes used were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan (Chen et al., Reference Chen, Su, Chen, Hsu, Huang, Chang and Bai2013; Chen et al., Reference Chen, Pan, Hsu, Huang, Su, Li, Lin, Tsai, Chang, Chen and Bai2016; Chen et al., Reference Chen, Hsu, Huang, Bai, Ko, Su, Li, Lin, Tsai, Pan, Chang and Chen2018; Cheng et al., Reference Cheng, Chang, Chen, Tsai, Su, Li, Tsai, Hsu, Huang, Lin, Chen and Bai2018). Taipei Veterans General Hospital institutional review board approved this study.
Inclusion criteria and disease classifications
All individuals with bipolar disorder (ICD-9-CM codes: 296 except 296.2, 296.3, 296.9, and 296.82) given by board-certificated psychiatrists were identified between 2001 and 2011 as the bipolar patients. FDRs of bipolar patients, including parents, offspring, and siblings, were assessed for the presence or absence of major psychiatric disorders. Major psychiatric disorders included ASD (ICD-9-CM code: 299), ADHD (ICD-9-CM code: 314), schizophrenia (ICD-9-CM code: 295), bipolar disorder, and MDD (ICD-9-CM codes: 296.2 and 296.3). All psychiatric disorders were diagnosed at least twice by board-certificated psychiatrists based on their clinical judgement and diagnostic interviews.
Statistical analysis
We used independent t tests for continuous variables and Pearson's χ2 tests for nominal variables to assess the differences between the FDRs of patients with bipolar disorder and the total population. The relative risks (RRs) and 95% CIs of five major psychiatric disorders (ASD, ADHD, schizophrenia, bipolar disorder, and MDD) were calculated among FDRs of patients with bipolar disorder compared with the total population after adjusting for demographic data (age, sex, residence, and income). Age, sex, income, residence significantly differed between FDRs of patients with bipolar disorder and the total population. Clustering effect from the measurements taken on multiple subjects within one family may existent in our study. In order to manage the clustering effect, modified Poisson regression analysis with the robust variance estimation was an appropriate method for estimating the RRs in the clustered data (Zou, Reference Zou2004; Yelland et al., Reference Yelland, Salter and Ryan2011). The modified Poisson regression uses a log link and has the equation: log (π i) = β 0 + β 1X1i + β 2X2i + …… + β kXki, where πi is the probability of experiencing the outcome of interest for subject i, and X 1i, X 2i, … X ki are predictor variables. However, the modified Poisson regression applies a Poisson distribution to the data, which produces consistent estimates of the parameters in the above equation but inconsistent variances, since the variance under a Poisson model is larger than the variance under a binomial model unless the outcome is rare. Robust variance estimation is therefore used to avoid overestimating standard errors of parameter estimates (Zou, Reference Zou2004; Yelland et al., Reference Yelland, Salter and Ryan2011). We further assessed the dose-dependent relationship between the risks of major psychiatric disorders and the numbers of bipolar patients (1 or ⩾2) among FDRs of patients with bipolar disorder. Finally, stratified by different familial kinships (parents, offspring, siblings, and twins), the RRs and 95% CIs of five major psychiatric disorders (ASD, ADHD, schizophrenia, bipolar disorder, and MDD) were calculated between FDRs with or without bipolar patients. All tests were two-tailed and result with p < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS Version 21.0 for Windows (IBM, Armonk, NY, USA) and SAS Version 9.2 (SAS Institute, Cary, NC, USA).
Results
Among the entire population in Taiwan, 72 573 patients with bipolar disorder and 188 290 FDRs of patients with bipolar disorder were identified in our study (Table 1). FDRs of bipolar patients had a higher prevalence of schizophrenia (1.67% v. 0.65%, p < 0.001), bipolar disorder (2.51% v. 0.42%, p < 0.001), MDD (3.75% v. 1.40%, p < 0.001), ASD (0.26% v. 0.12%, p < 0.001), and ADHD (1.46% v. 0.65%, p < 0.001) compared with the total population (Table 2). FDRs of patients with bipolar disorder were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 6.12, 95% CI 5.95–6.30), MDD (RR 2.89, 95% CI 2.82–2.96), schizophrenia (RR 2.64, 95% CI 2.55–2.73), ADHD (RR 2.21, 95% CI 2.13–2.30), and ASD (RR 2.10, 95% CI 1.92–2.29), than the total population did after adjusting for demographic data (Table 2). In addition, a dose-dependent association was found between risk of each major psychiatric disorder, including bipolar disorder (1: RR 6.10, 95% CI 5.92–6.29; ⩾2: 29.10, 95% CI 25.87–32.7), MDD (RR 2.88, 95% CI 2.81–2.94; RR 7.71, 95% CI 6.75–8.81), schizophrenia (RR 2.59, 95% CI 2.50–2.69; RR 8.78, 95% CI 7.41–10.39), ADHD (RR 2.22, 95% CI 2.14–2.31; RR 3.47, 95% CI 2.67–4.49), and ASD (RR 2.04, 95% CI 1.87–2.24; RR 7.11, 95% CI 4.72–10.70), and the numbers of bipolar patients (Table 3).
Table 1. Demographic characteristics among FDRs of patients with bipolar disorder and the total population
FDRs, first-degree relatives; s.d., standard deviation; USD, US dollar; RR, relative risk; CI, confidence interval.
1 US dollar (USD) = 31.63 New Taiwan Dollar.
Bold type indicates the statistical significance.
Table 2. Relative risks of major psychiatric disorders among FDRs of patients with bipolar disorder and the total population
FDRs, first-degree relatives; RR, relative risk; CI, confidence interval; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; MDD, Major depressive disorder.
Bold type indicates the statistical significance.
Table 3. The dose-dependent relationship between the risks of major psychiatric disorders and the numbers of bipolar patients among FDRs of patients with bipolar disorder
FDRs, first-degree relatives; RR, relative risk; CI, confidence interval; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; MDD, Major depressive disorder.
Bold type indicates the statistical significance.
Figure 1 reported the risks of five major psychiatric disorders among FDRs (parents, offspring, siblings, and twins) of patients with bipolar disorder. The parents, the offspring, the siblings, and the twins of patients with bipolar disorder had an increased risk (RR, 95% CI) of each major psychiatric disorders, including bipolar disorder (parents of patients with bipolar disorder: 6.69, 6.37–7.02; offspring: 6.38, 6.06–6.71; siblings: 7.26, 6.91–7.63; twins: 41.86, 32.78–53.5), schizophrenia (parents: 3.31, 3.13–3.51; offspring: 3.19, 2.97–3.43; siblings: 3.89, 3.68–4.12; twins: 16.93, 12.56–22.8), MDD (parents: 3.00, 2.87–3.13; offspring: 2.79, 2.69–2.89; siblings: 3.31, 3.17–3.46; twins: 8.12, 5.90–11.17), ADHD (parents: 2.30, 2.21–2.40; offspring: 2.87, 2.06–3.99; siblings: 1.81, 1.67–1.96; twins: 5.26, 3.42–8.09), and ASD (parents: 1.96, 1.75–2.18; offspring: 6.77, 2.98–15.4; siblings: 2.51, 2.14–2.94; twins: 18.83, 11.01–32.2), compared with FDRs without bipolar disorder patients (Fig. 1, online Supplementary Tables S1–S5).
Fig. 1. Relative risks for major psychiatric disorder among FDRs of patients with bipolar disorder by different kinships.
Discussion
Our results supported the study hypotheses that the FDRs, including parents, offspring, siblings, and twins, of patients with bipolar disorder have increased risks of being diagnosed with schizophrenia, bipolar disorder, MDD, ADHD, and ASD. The co-twins of patients with bipolar disorder had the highest risks of those five major psychiatric disorders. A dose-dependent relationship was found between the risks of the five major psychiatric disorders and the numbers of bipolar patients. In addition, the coaggregation risk of bipolar disorder was highest with bipolar disorder, followed by MDD, schizophrenia, ADHD, and ASD.
As mentioned in the Introduction section, the offspring and siblings of patients with bipolar disorder are more likely to have bipolar disorder and other major psychiatric disorders, including schizophrenia, MDD, and ADHD (Birmaher et al., Reference Birmaher, Axelson, Monk, Kalas, Goldstein, Hickey, Obreja, Ehmann, Iyengar, Shamseddeen, Kupfer and Brent2009; Birmaher et al., Reference Birmaher, Axelson, Goldstein, Monk, Kalas, Obreja, Hickey, Iyengar, Brent, Shamseddeen, Diler and Kupfer2010; Axelson et al., Reference Axelson, Goldstein, Goldstein, Monk, Yu, Hickey, Sakolsky, Diler, Hafeman, Merranko, Iyengar, Brent, Kupfer and Birmaher2015; Song et al., Reference Song, Bergen, Kuja-Halkola, Larsson, Landen and Lichtenstein2015). The Pittsburgh Bipolar Offspring Study evaluated the lifetime prevalence of psychiatric disorders in the preschool- and school-aged offspring of parents with bipolar disorders and found that the offspring of parents with bipolar disorder had elevated risks of bipolar disorder (OR 13.4, 95% CI 2.9–61.6), depressive disorder (OR 2.1, 95% CI 0.9–4.9), and ADHD (OR 3.5, 95% CI 1.1–11.4) (Birmaher et al., Reference Birmaher, Axelson, Monk, Kalas, Goldstein, Hickey, Obreja, Ehmann, Iyengar, Shamseddeen, Kupfer and Brent2009; Birmaher et al., Reference Birmaher, Axelson, Goldstein, Monk, Kalas, Obreja, Hickey, Iyengar, Brent, Shamseddeen, Diler and Kupfer2010). A study examining Swedish families demonstrated that the siblings of patients with bipolar disorder had increased risks of schizophrenia, bipolar disorder, MDD, ADHD, and ASD (Song et al., Reference Song, Bergen, Kuja-Halkola, Larsson, Landen and Lichtenstein2015). The findings of the present study are consistent with the previous findings of the association between parental bipolar disorders and bipolar disorder, MDD, and ADHD in offspring. Furthermore, we found that the offspring, both sons and daughters, of parents with bipolar disorder had higher risks of schizophrenia and ASD than those without parents having bipolar disorder. Regarding the risks of major psychiatric disorders among the siblings of patients with bipolar disorder, we demonstrated that the co-twins of patients with bipolar disorder had the highest risks of schizophrenia, bipolar disorder, MDD, ADHD, and ASD. A few studies have investigated the risk of psychiatric disorders, except for bipolar disorder, among the parents of patients with bipolar disorder (Sucksdorff et al., Reference Sucksdorff, Chudal, Suominen, Jokiranta, Brown and Sourander2014; Song et al., Reference Song, Bergen, Kuja-Halkola, Larsson, Landen and Lichtenstein2015). Sucksdorff et al. assessed 1861 patients with bipolar disorder aged up to 25 years, 3643 matched controls, and their parents, and revealed that the parental psychiatric diagnoses of bipolar disorder [OR (maternal): 5.2, 95% CI 2.52–10.62; OR (paternal): 8.1, 95% CI 3.77–17.26] and schizophrenia [OR (maternal): 3.1, 95% CI 1.69–5.84; OR (paternal): 4.5, 95% CI 1.97–10.27] were associated with bipolar disorder in offspring (Sucksdorff et al., Reference Sucksdorff, Chudal, Suominen, Jokiranta, Brown and Sourander2014). In addition to parental schizophrenia and bipolar disorder, we found that both fathers and mothers of patients with bipolar disorder were likely to have MDD and ADHD, and the mothers of patients with bipolar disorder additionally had a higher risk of ASD. On the basis of the aforementioned evidence, we can conclude bipolar disorder coaggregates with other major psychiatric disorders, including schizophrenia, MDD, ADHD, and ASD, within families.
Increasing evidence supports that schizophrenia, bipolar disorder, MDD, ASD, and ADHD may share some common genes and underlying pathophysiology in the neurodevelopmental process. To examine this shared genetic etiology, the Cross-Disorder Group of the Psychiatric Genomics Consortium analyzed genome-wide single-nucleotide polymorphism (SNP) data for schizophrenia, bipolar disorder, MDD, ASD, and ADHD in 33 332 patients and 27 888 controls of European ancestry and reported that SNPs at four loci exceeded the cutoff value for genome-wide significance in the analysis (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013b). Furthermore, they reported that SNPs explained 17–29% of the variance in liability and revealed that the genetic correlation, which was calculated using common SNPs, was high between bipolar disorder and schizophrenia (0.68 ± 0.04 s.e., p < 10−16), moderate between bipolar disorder and MDD (0.47 ± 0.06 s.e., p = 1.5 × 10−14), and low between bipolar disorder and ADHD (0.05 ± 0.05 s.e., p = 0.31) and ASD (0.04 ± 0.06 s.e., p = 0.53) (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013a). This GWAS provided convincing evidence that specific genes shared by major psychiatric disorders are hereditary in a family and result in the highly variable endophenotypes of psychiatric disorders. Our findings supported the results of the GWAS, which reported a significant coaggregation of bipolar disorder with schizophrenia and MDD. However, we also indicated a significant coaggregation of bipolar disorder with ADHD and ASD, but only a low genetic association was noted in the GWAS. Establishing the differences between the genetic level and the clinical or psychopathological level requires further investigation.
This study has several limitations. First, the prevalence of major psychiatric disorders may be underestimated because only those who sought medical consultation and help are identified in the database. However, medical services are easily accessible in Taiwan because of the high coverage and affordability of Taiwan NHI. In addition, in our study, the diagnoses of major psychiatric disorders were made by board-certificated psychiatrists, yielding higher diagnostic validity. In our study, prevalence estimates calculated for the disorders in the total population were considerably lower than those found in the majority of population-based studies in the USA and in Europe. The much lower prevalence of bipolar disorder and MDD in Taiwanese population was reported in the previous cross-national study (Weissman et al., Reference Weissman, Bland, Canino, Faravelli, Greenwald, Hwu, Joyce, Karam, Lee, Lellouch, Lepine, Newman, Rubio-Stipec, Wells, Wickramaratne, Wittchen and Yeh1996). The reasons for the low prevalence of psychiatric disorders, such as bipolar disorder and MDD, required further investigation. Second, in our study, we defined twins as those with the same birthdate and the same mother in the database; thus, homozygotes or heterozygotes could not be differentiated because homozygote or heterozygote state would not be recorded in NHIRD. Based on the concept of genetics, the homozygote sibling of a twin with bipolar disorder should exhibit the higher likelihood of having major psychiatric disorders than the heterozygote sibling of a twin with bipolar disorder. Additional clinical twin-based studies are required to validate our findings and further inference. In addition, some other factors, such as education level and environmental factors, are not available in the Taiwan NHIRD. Without this information, we cannot assess their impact. Third, because the specific diagnostic code of bipolar II disorder is not available in the ICD-9-code system in Taiwan NHIRD, we were unable to differentiate between bipolar I disorder and bipolar II disorder in the current study. Some previous studies suggested that bipolar I disorder and bipolar II disorder may display different familial aggregation patterns; bipolar I disorder is highly heritable and bipolar II disorder is not (Merikangas et al., Reference Merikangas, Cui, Heaton, Nakamura, Roca, Ding, Qin, Guo, Shugart, Zarate and Angst2014; Vandeleur et al., Reference Vandeleur, Merikangas, Strippoli, Castelao and Preisig2014). Further study would be necessary to elucidate the possible different familial coaggregation patterns of bipolar I disorder and bipolar II disorder with other psychiatric disorders. Fourth, we only focused on the familial coaggregation of bipolar disorder with schizophrenia, MDD, ASD, and ADHD in our study. Whether bipolar disorder may be co-aggregated with other psychiatric disorders, such as anxiety disorders, required further investigation. Fifth, because something is shown to be familial may not mean that this is necessarily a genetic relationship. Many other dynamics, such shared environment factors, are potentially conveyed in families over and above shared genes. Further studies would be necessary to elucidate non-genetic factors in the familial coaggregation of bipolar disorder with other major psychiatric disorders.
In conclusion, the FDRs, including parents, offspring, siblings, and twins, of patients with bipolar disorder have a higher likelihood of schizophrenia, bipolar disorder, MDD, ADHD, and ASD after adjustment for demographic data. The association between the risk of each major psychiatric disorder and the numbers of bipolar patients is dose-dependent. Our findings indicated a coaggregation of bipolar disorder with other major psychiatric disorders in a family and were consistent with the GWAS results that schizophrenia, bipolar disorder, MDD, ADHD, and ASD share common genes. Furthermore, given the increased risks of major psychiatric disorders, our results encourage clinicians and state mental health institutions to pay more attention to the mental health of the FDRs of patients with bipolar disorder. Early identification of the risk of mental illnesses would be helpful for early prevention and intervention among the FDRs of patients with bipolar disorder.
Author ORCIDs
Mu-Hong Chen 0000-0001-6516-1073.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S003329171800332X.
Acknowledgements
We thank Mr I-Fan Hu for his friendship and support. We thank Dr MHC, Dr TPS, and Dr YMB, who designed the study and wrote the protocol, Dr MHC, who wrote the manuscripts, Dr SJT, Dr JWH, Dr KLH, Dr CMC, Dr CTL, Prof TLP, Prof PWW, and Dr WCL, who assisted with the literature review, and preparation and proof-reading of the manuscript, and Dr YMB, Dr TJC, Miss WHC, and Dr MHC, who performed the statistical analysis and provided the advice on statistical analysis. All authors have no financial relationships relevant to this article to disclose. The study was supported by grant from Taipei Veterans General Hospital (V103E10-001, V104E10-002, V105E10-001-MY2-1, V105A-049, V106B-020, V107B-010, V107C-181) and Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3). The funding source had no role in any process of our study.
Author contributions
Dr Mu-Hong Chen, Dr Tung-Ping Su, and Dr Ya-Mei Bai designed the study and wrote the protocol. Dr Mu-Hong Chen wrote the manuscripts; Dr Ju-Wei Hsu, Dr Kai-Lin Huang, Dr Shih-Jen Tsai, Dr Cheng-Ta Li, Dr Chih-Ming Cheng, Prof Tai-Long Pan, Prof Pei-Wen Wang, and Dr Wei-Chen Lin assisted with the literature reviews, and preparation and proof-reading of the manuscript; Dr Ya-Mei Bai, Dr Tzeng-Ji Chen, Miss Wen-Han Chang, and Dr Mu-Hong Chen performed the statistical analysis and provided the advice on statistical analysis.
Conflict of interest
No conflict of interest.
