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Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study

Molecular Psychiatry volume 23, pages 1756–1763 (2018)Cite this article

Abstract

A previous genetic study has suggested that schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) share common disease-associated genes. However, whether individuals with first-degree relatives (FDRs) with schizophrenia have a higher risk of these major psychiatric disorders requires further investigation. This study used Taiwan’s National Health Insurance Research Database and identified 151 650 patients with schizophrenia and 227 967 individuals with FDRs with schizophrenia. The relative risks (RRs) of schizophrenia and other major psychiatric disorders were assessed in individuals with FDRs with schizophrenia. The individuals with FDRs with schizophrenia exhibited higher RRs (95% confidence interval) of major psychiatric disorders, namely schizophrenia (4.76, 4.65–4.88), bipolar disorder (3.23, 3.12–3.35), major depressive disorder (2.05, 2.00–2.10), ASD (2.55, 2.35–2.77) and ADHD (1.31, 1.25–1.37) than were found in the total population. Several sensitivity analyses were conducted to confirm these results. A dose-dependent relationship was observed between the risks of major psychiatric disorders and the numbers of FDRs with schizophrenia. The increased risks of major psychiatric disorders were consistent in different family relationships, namely among parents, offspring, siblings and twins. Our study supports the familial dose-dependent co-aggregation of schizophrenia, bipolar disorder, major depressive disorder, ASD and ADHD, and our results may prompt governmental public health departments and psychiatrists to focus on the mental health of individuals with FDRs with schizophrenia.

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References

  1. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.

    Article  Google Scholar 

  2. Ingraham LJ, Kugelmass S, Frenkel E, Nathan M, Mirsky AF. Twenty-five-year followup of the Israeli High-Risk Study: current and lifetime psychopathology. Schizophr Bull 1995; 21: 183–192.

    Article  CAS  Google Scholar 

  3. Onstad S, Skre I, Edvardsen J, Torgersen S, Kringlen E. Mental disorders in first-degree relatives of schizophrenics. Acta Psychiatr Scand 1991; 83: 463–467.

    Article  CAS  Google Scholar 

  4. Hans SL, Auerbach JG, Styr B, Marcus J. Offspring of parents with schizophrenia: mental disorders during childhood and adolescence. Schizophr Bull 2004; 30: 303–315.

    Article  Google Scholar 

  5. Van Snellenberg JX, de Candia T. Meta-analytic evidence for familial coaggregation of schizophrenia and bipolar disorder. Arch Gen Psychiatry 2009; 66: 748–755.

    Article  Google Scholar 

  6. Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 234–239.

    Article  CAS  Google Scholar 

  7. Owen MJ, Craddock N, Jablensky A. The genetic deconstruction of psychosis. Schizophr Bull 2007; 33: 905–911.

    Article  Google Scholar 

  8. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr Bull 2009; 35: 383–402.

    Article  Google Scholar 

  9. Chisholm K, Lin A, Abu-Akel A, Wood SJ. The association between autism and schizophrenia spectrum disorders: a review of eight alternate models of co-occurrence. Neurosci Biobehav Rev 2015; 55: 173–183.

    Article  Google Scholar 

  10. Dean K, Stevens H, Mortensen PB, Murray RM, Walsh E, Pedersen CB. Full spectrum of psychiatric outcomes among offspring with parental history of mental disorder. Arch Gen Psychiatry 2010; 67: 822–829.

    Article  Google Scholar 

  11. Mortensen PB, Pedersen MG, Pedersen CB. Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant? Psychol Med 2010; 40: 201–210.

    Article  CAS  Google Scholar 

  12. Rasic D, Hajek T, Alda M, Uher R. Risk of mental illness in offspring of parents with schizophrenia, bipolar disorder, and major depressive disorder: a meta-analysis of family high-risk studies. Schizophr Bull 2014; 40: 28–38.

    Article  Google Scholar 

  13. Sanchez-Gistau V, Romero S, Moreno D, de la Serna E, Baeza I, Sugranyes G et al. Psychiatric disorders in child and adolescent offspring of patients with schizophrenia and bipolar disorder: a controlled study. Schizophr Res 2015; 168: 197–203.

    Article  Google Scholar 

  14. Chou IJ, Kuo CF, Huang YS, Grainge MJ, Valdes AM, See LC et al. Familial aggregation and heritability of schizophrenia and co-aggregation of psychiatric illnesses in affected families. Schizophr Bull 2017; 43: 1070–1078.

    Article  Google Scholar 

  15. Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379.

    Article  Google Scholar 

  16. Gottesman II, Laursen TM, Bertelsen A, Mortensen PB. Severe mental disorders in offspring with 2 psychiatrically ill parents. Arch Gen Psychiatry 2010; 67: 252–257.

    Article  Google Scholar 

  17. Jokiranta E, Brown AS, Heinimaa M, Cheslack-Postava K, Suominen A, Sourander A. Parental psychiatric disorders and autism spectrum disorders. Psychiatry Res 2013; 207: 203–211.

    Article  Google Scholar 

  18. Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148: 1223–1241.

    Article  CAS  Google Scholar 

  19. Niemi LT, Suvisaari JM, Haukka JK, Wrede G, Lonnqvist JK. Cumulative incidence of mental disorders among offspring of mothers with psychotic disorder. Results from the Helsinki High-Risk Study. Br J Psychiatry 2004; 185: 11–17.

    Article  Google Scholar 

  20. Pettersson E, Larsson H, Lichtenstein P. Common psychiatric disorders share the same genetic origin: a multivariate sibling study of the Swedish population. Mol Psychiatry 2016; 21: 717–721.

    Article  CAS  Google Scholar 

  21. Chen MH, Chen YS, Hsu JW, Huang KL, Li CT, Lin WC et al. Comorbidity of ADHD and subsequent bipolar disorder among adolescents and young adults with major depression: a nationwide longitudinal study. Bipolar Disord 2015; 17: 315–322.

    Article  Google Scholar 

  22. Cheng CM, Wu YH, Tsai SJ, Bai YM, Hsu JW, Huang KL et al. Risk of developing Parkinson's disease among patients with asthma: a nationwide longitudinal study. Allergy 2015; 70: 1605–1612.

    Article  Google Scholar 

  23. Li CT, Bai YM, Huang YL, Chen YS, Chen TJ, Cheng JY et al. Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study. Br J Psychiatry 2012; 200: 45–51.

    Article  Google Scholar 

  24. Chen MH, Lan WH, Hsu JW, Huang KL, Su TP, Li CT et al. Risk of developing type 2 diabetes in adolescents and young adults with autism spectrum disorder: anationwide longitudinal study. Diabetes Care 2016; 39: 788–793.

    Article  CAS  Google Scholar 

  25. Kuo CF, Grainge MJ, Valdes AM, See LC, Luo SF, Yu KH et al. Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med 2015; 175: 1518–1526.

    Article  Google Scholar 

  26. Kuo CF, Grainge MJ, Valdes AM, See LC, Luo SF, Yu KH et al. Familial risk of Sjogren's syndrome and co-aggregation of autoimmune diseases in affected families: a nationwide population study. Arthritis Rheumatol 2015; 67: 1904–1912.

    Article  Google Scholar 

  27. Liu CYHY, Chuang YL, Chen YJ, Weng WS, Liu JS. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag 2006; 14: 1–22.

    Google Scholar 

  28. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004; 159: 702–706.

    Article  Google Scholar 

  29. Cross-Disorder Group of the Psychiatric Genomics CCross-Disorder Group of the Psychiatric Genomics CLee SH, Cross-Disorder Group of the Psychiatric Genomics CRipke S, Cross-Disorder Group of the Psychiatric Genomics CNeale BM, Cross-Disorder Group of the Psychiatric Genomics CFaraone SV, Cross-Disorder Group of the Psychiatric Genomics CPurcell SM et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984–994.

    Article  Google Scholar 

  30. Karege F, Meary A, Perroud N, Jamain S, Leboyer M, Ballmann E et al. Genetic overlap between schizophrenia and bipolar disorder: a study with AKT1 gene variants and clinical phenotypes. Schizophr Res 2012; 135: 8–14.

    Article  Google Scholar 

  31. Muller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL. Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia. Bipolar Disord 2011; 13: 198–207.

    Article  CAS  Google Scholar 

  32. Peerbooms OL, van Os J, Drukker M, Kenis G, Hoogveld L et alGroup MiP. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun 2011; 25: 1530–1543.

  33. Francks C, Tozzi F, Farmer A, Vincent JB, Rujescu D St, Clair D et al. Population-based linkage analysis of schizophrenia and bipolar case-control cohorts identifies a potential susceptibility locus on 19q13. Mol Psychiatry 2010; 15: 319–325.

    Article  CAS  Google Scholar 

  34. Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen-White KR, Rosso A et al. A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19. Mol Psychiatry 2002; 7: 851–859.

    Article  CAS  Google Scholar 

  35. Larsson H, Ryden E, Boman M, Langstrom N, Lichtenstein P, Landen M. Risk of bipolar disorder and schizophrenia in relatives of people with attention-deficit hyperactivity disorder. Br J Psychiatry 2013; 203: 103–106.

    Article  Google Scholar 

  36. de la Serna E, Baeza I, Toro J, Andres S, Puig O, Sanchez-Guistau V et al. Relationship between clinical and neuropsychological characteristics in child and adolescent first degree relatives of subjects with schizophrenia. Schizophr Res 2010; 116: 159–167.

    Article  Google Scholar 

  37. Keshavan M, Montrose DM, Rajarethinam R, Diwadkar V, Prasad K, Sweeney JA. Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments. Schizophr Res 2008; 103: 114–120.

    Article  Google Scholar 

  38. Barch DM. The cognitive neuroscience of schizophrenia. Annu Rev Clin Psychol 2005; 1: 321–353.

    Article  Google Scholar 

  39. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 2005; 57: 1336–1346.

    Article  Google Scholar 

  40. Jokiranta-Olkoniemi E, Cheslack-Postava K, Sucksdorff D, Suominen A, Gyllenberg D, Chudal R et al. Risk of psychiatric and neurodevelopmental disorders among siblings of probands with autism spectrum disorders. JAMA Psychiatry 2016; 73: 622–629.

    Article  Google Scholar 

  41. Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M et al. Parental psychiatric disorders associated with autism spectrum disorders in the offspring. Pediatrics 2008; 121: e1357–e1362.

    Article  Google Scholar 

  42. Foss-Feig JH, Adkinson BD, Ji JL, Yang G, Srihari VH, McPartland JC et al. Searching forcross-diagnostic convergence: neural mechanisms governing excitation and inhibition balance in schizophrenia and autism spectrum disorders. Biol Psychiatry 2017; 81: 848–861.

    Article  Google Scholar 

  43. Liu X, Li Z, Fan C, Zhang D, Chen J. Genetics implicate common mechanisms in autism and schizophrenia: synaptic activity and immunity. J Med Genet 2017; 54: 511–520.

    CAS  PubMed  Google Scholar 

  44. Carroll LS, Owen MJ. Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med 2009; 1: 102.

    Article  Google Scholar 

  45. Schneider M, Debbane M, Bassett AS, Chow EW, Fung WL, van den Bree M et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry 2014; 171: 627–639.

    Article  Google Scholar 

  46. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet 2016; 388: 86–97.

    Article  Google Scholar 

  47. Sivakumaran S, Agakov F, Theodoratou E, Prendergast JG, Zgaga L, Manolio T et al. Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet 2011; 89: 607–618.

    Article  CAS  Google Scholar 

  48. Autism, Developmental Disabilities Monitoring Network Surveillance Year Principal I, Centers for Disease C, Prevention. Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR Surveill Summ 2007; 56: 12–28.

    Google Scholar 

  49. Lai MC, Baron-Cohen S. Identifying the lost generation of adults with autism spectrum conditions. Lancet Psychiatry 2015; 2: 1013–1027.

    Article  Google Scholar 

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Acknowledgments

We thank Mr I-Fan Hu for his friendship and support. We thank Dr MHC, Dr CMC, Miss WHC and Dr YMB, who designed the study and wrote the protocol; Dr CMC and Dr MHC, who wrote the manuscript; Dr CFT, Dr SJT, Dr JWH, Dr KLH, Dr CTL 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 and provided advice on the statistical analysis. The study was supported by grants from the Taipei Veterans General Hospital (V103E10-001, V104E10-002, V105E10-001-MY2-1, V105D10-001-MY2-2, V106-C-079, V105A-049, V106B-020) and the Ministry of Science and Technology (MOST105-2314-B-075-025-MY3).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan

    C-M Cheng, W-H Chang, M-H Chen, C-F Tsai, T-P Su, C-T Li, S-J Tsai, J-W Hsu, K-L Huang, W-C Lin & Y-M Bai

  2. Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    C-M Cheng, M-H Chen, C-F Tsai, T-P Su, C-T Li, S-J Tsai, J-W Hsu, K-L Huang, W-C Lin & Y-M Bai

  3. Graduate Institute of Statistics National Central University, Taoyuan, Taiwan

    W-H Chang

  4. Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

    M-H Chen, C-F Tsai, T-P Su, C-T Li & W-C Lin

  5. Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan

    T-P Su

  6. Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    T-J Chen

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Contributions

Dr Mu-Hong Chen, Dr Chih-Ming Cheng, Miss Wen-Han Chang and Dr Ya-Mei Bai designed the study and wrote the protocol. Dr Mu-Hong Chen and Dr Chih-Ming Cheng wrote the manuscript. Dr Tung-Ping Su, Dr Ju-Wei Hsu, Dr Kai-Lin Huang, Dr Chia-Fen Tsai, Dr Shih-Jen Tsai, Dr Cheng-Ta Li and Dr Wei-Chen Lin assisted with the literature review 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 and provided advice on the statistical analysis.

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Correspondence to M-H Chen or Y-M Bai.

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Cheng, CM., Chang, WH., Chen, MH. et al. Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. Mol Psychiatry 23, 1756–1763 (2018). https://doi.org/10.1038/mp.2017.217

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