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Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework

Molecular Psychiatry volume 10, pages 6–13 (2005)Cite this article

Abstract

Schizophrenia has long been thought to be clinically heterogeneous. A range of studies suggests that this is due to genetic heterogeneity. Some clinical features, such as negative symptoms, are associated with a greater risk of illness in relatives. Affected sibling pairs are correlated for clinical and course features as well as subforms of illness, and twin studies suggest that this is due to genetic factors. This is further supported by findings that subjects from families linked to some chromosomal regions may differ clinically from those from unlinked families. Moreover, some genes may affect clinical features without altering susceptibility (ie are modifier genes). High-risk genotypes may have quantitative, rather than categorical effects, and may influence milder or subclinical phenotypes. Another recent finding is that nonpsychotic relatives may have personality features that resemble those of their affected relatives. These findings taken together suggest that there may be several classes of gene action in schizophrenia: some genes may influence susceptibility only, others may influence clinical features only, and still others may have a mixed effect. Furthermore, subsets of these classes may affect personality and other traits in nonpsychotic relatives. Understanding these classes of gene action may help guide the design of linkage and association studies that have increased power. We describe five classes of genes and their predictions of the outcomes of family, twin, and several types of linkage studies. We go on to explore how these predictions can in turn be used to aid in the design of linkage studies.

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References

  1. Harrison PJ, Owen MJ . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–419.

    Article  CAS  PubMed  Google Scholar 

  2. Kraepelin E . Manic-Depressive Illiness and Paranoia. Edinburgh, E & S Livingstone: Scotland, 1921.

    Google Scholar 

  3. McGlashan TH, Fenton WS . Classical subtypes for schizophrenia: literature review for DSM-IV. Schizophr Bull 1991; 17: 609–632.

    Article  CAS  PubMed  Google Scholar 

  4. Peralta V, Cuesta MJ . How many and which are the psychopathological dimensions in schizophrenia? Issues influencing their ascertainment. Schizophr Res 2001; 49: 269–285.

    Article  CAS  PubMed  Google Scholar 

  5. Malaspina D, Goetz RR, Yale S, Berman A, Friedman JH, Tremeau F et al. Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome. Am J Psychiatry 2000; 157: 994–1003.

    Article  CAS  PubMed  Google Scholar 

  6. Cardno AG, Thomas K, McGuffin P . Clinical variables and genetic loading for schizophrenia: analysis of published Danish adoption study data. Schizophr Bull 2002; 28: 393–399.

    Article  PubMed  Google Scholar 

  7. Kirkpatrick B, Ross DE, Walsh D, Karkowski L, Kendler KS . Family characteristics of deficit and nondeficit schizophrenia in the Roscommon Family Study. Schizophr Res 2000; 45: 57–64.

    Article  CAS  PubMed  Google Scholar 

  8. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter Jr WT . A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 2001; 58: 165–171.

    Article  CAS  PubMed  Google Scholar 

  9. Kendler KS, McGuire M, Gruenberg AM, Walsh D . Clinical heterogeneity in schizophrenia and the pattern of psychopathology in relatives: results from an epidemiologically based family study. Acta Psychiatr Scand 1994; 89: 294–300.

    Article  CAS  PubMed  Google Scholar 

  10. Kendler KS, Karkowski-Shuman L, O’Neill FA, Straub RE, MacLean CJ, Walsh D . Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of high-density schizophrenia families: evidence for possible etiologic heterogeneity. Am J Psychiatry 1997; 154: 191–198.

    Article  CAS  PubMed  Google Scholar 

  11. Loftus J, DeLisi LE, Crow TJ . Factor structure and familiality of first-rank symptoms in sibling pairs with schizophrenia and schizoaffective disorder. Br J Psychiatry 2000; 177: 15–19.

    Article  CAS  PubMed  Google Scholar 

  12. Cardno AG, Jones LA, Murphy KC, Sanders RD, Asherson P, Owen MJ et al. Dimensions of psychosis in affected sibling pairs. Schizophr Bull 1999; 25: 841–850.

    Article  CAS  PubMed  Google Scholar 

  13. 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  PubMed  Google Scholar 

  14. Cardno AG, Sham PC, Farmer AE, Murray RM, McGuffin P . Heritability of Schneider's first-rank symptoms. Br J Psychiatry 2002; 180: 35–38.

    Article  PubMed  Google Scholar 

  15. Cardno AG, Sham PC, Murray RM, McGuffin P . Twin study of symptom dimensions in psychoses. Br J Psychiatry 2001; 179: 39–45.

    Article  CAS  PubMed  Google Scholar 

  16. Kendler KS, Myers JM, O’Neill FA, Martin R, Murphy B, MacLean CJ et al. Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of high-density schizophrenia families. Am J Psychiatry 2000; 157: 402–408.

    Article  CAS  PubMed  Google Scholar 

  17. Chiu YF, McGrath JA, Thornquist MH, Wolyniec PS, Nestadt G, Swartz KL et al. Genetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q. Mol Psychiatry 2002; 7: 658–664.

    Article  CAS  PubMed  Google Scholar 

  18. Kaiser R, Konneker M, Henneken M, Dettling M, Muller-Oerlinghausen B, Roots I et al. Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry 2000; 5: 418–424.

    Article  CAS  PubMed  Google Scholar 

  19. Serretti A, Lilli R, Lorenzi C, Lattuada E, Smeraldi E . DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects. Am J Med Genet 2001; 105: 283–290.

    Article  CAS  PubMed  Google Scholar 

  20. Serretti A, Lattuada E, Lorenzi C, Lilli R, Smeraldi E . Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. Mol Psychiatry 2000; 5: 270–274.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang XY, Zhou DF, Zhang PY, Wei J . The CCK-A receptor gene possibly associated with positive symptoms of schizophrenia. Mol Psychiatry 2000; 5: 239–240.

    Article  CAS  PubMed  Google Scholar 

  22. Malhotra AK, Goldman D, Mazzanti C, Clifton A, Breier A, Pickar D . A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol Psychiatry 1998; 3: 328–332.

    Article  CAS  PubMed  Google Scholar 

  23. Fanous AH, Neale MC, Straub RE, Webb BT, O’Neill AF, Walsh D et al. Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet 2004; 125B: 69–78.

    Article  PubMed  Google Scholar 

  24. Cardno AG, Bowen T, Guy CA, Jones LA, McCarthy G, Williams NM et al. CAG repeat length in the hKCa3 gene and symptom dimensions in schizophrenia. Biol Psychiatry 1999; 45: 1592–1596.

    Article  CAS  PubMed  Google Scholar 

  25. Riazuddin S, Castelein CM, Ahmed ZM, Lalwani AK, Mastroianni MA, Naz S et al. Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nat Genet 2000; 26: 431–434.

    Article  CAS  PubMed  Google Scholar 

  26. Salvatore F, Scudiero O, Castaldo G . Genotype–phenotype correlation in cystic fibrosis: the role of modifier genes. Am J Med Genet 2002; 111: 88–95.

    Article  PubMed  Google Scholar 

  27. DeStefano AL, Lew MF, Golbe LI, Mark MH, Lazzarini AM, Guttman M et al. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am J Hum Genet 2002; 70: 1089–1095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cardno AG, Holmans PA, Rees MI, Jones LA, McCarthy GM, Hamshere ML et al. A genomewide linkage study of age at onset in schizophrenia. Am J Med Genet 2001; 105: 439–445.

    Article  CAS  PubMed  Google Scholar 

  29. McGlashan TH, Fenton WS . Subtype progression and pathophysiologic deterioration in early schizophrenia. Schizophr Bull 1993; 19: 71–84.

    Article  CAS  PubMed  Google Scholar 

  30. Arndt S, Andreasen NC, Flaum M, Miller D, Nopoulos P . A longitudinal study of symptom dimensions in schizophrenia. Prediction and patterns of change. Arch Gen Psychiatry 1995; 52: 352–360.

    Article  CAS  PubMed  Google Scholar 

  31. Fanous A, Gardner C, Walsh D, Kendler KS . Relationship between positive and negative symptoms of schizophrenia and schizotypal symptoms in nonpsychotic relatives. Arch Gen Psychiatry 2001; 58: 669–673.

    Article  CAS  PubMed  Google Scholar 

  32. Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman M, Walsh D . The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives. Arch Gen Psychiatry 1993; 50: 781–788.

    Article  CAS  PubMed  Google Scholar 

  33. MacDonald III AW, Pogue-Geile MF, Johnson MK, Carter CS . A specific deficit in context processing in the unaffected siblings of patients with schizophrenia. Arch Gen Psychiatry 2003; 60: 57–65.

    Article  PubMed  Google Scholar 

  34. Park S, Holzman PS, Goldman-Rakic PS . Spatial working memory deficits in the relatives of schizophrenic patients. Arch Gen Psychiatry 1995; 52: 821–828.

    Article  CAS  PubMed  Google Scholar 

  35. Turetsky BI, Cannon TD, Gur RE . P300 subcomponent abnormalities in schizophrenia: III. Deficits In unaffected siblings of schizophrenic probands. Biol Psychiatry 2000; 47: 380–390.

    Article  CAS  PubMed  Google Scholar 

  36. Michie PT, Innes-Brown H, Todd J, Jablensky AV . Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders. Biol Psychiatry 2002; 52: 749–758.

    Article  PubMed  Google Scholar 

  37. Cannon TD, van Erp TG, Huttunen M, Lonnqvist J, Salonen O, Valanne L et al. Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 1998; 55: 1084–1091.

    Article  CAS  PubMed  Google Scholar 

  38. Staal WG, Hulshoff Pol HE, Schnack HG, Hoogendoorn ML, Jellema K, Kahn RS . Structural brain abnormalities in patients with schizophrenia and their healthy siblings. Am J Psychiatry 2002; 159: 244–250.

    Article  PubMed  Google Scholar 

  39. Siever LJ, Davis KL . The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 2004; 161: 398–413.

    Article  PubMed  Google Scholar 

  40. Avramopoulos D, Stefanis NC, Hantoumi I, Smyrnis N, Evdokimidis I, Stefanis CN . Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Mol Psychiatry 2002; 7: 706–711.

    Article  CAS  PubMed  Google Scholar 

  41. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS et al. Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60: 889–896.

    Article  CAS  PubMed  Google Scholar 

  42. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D . A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002; 159: 652–654.

    Article  PubMed  Google Scholar 

  44. Coppen A . Effects of a depressive illness on MPI scores. Br J Psychiatry 111; 236–239: 1965.

    Google Scholar 

  45. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ . A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry 1993; 50: 853–862.

    Article  CAS  PubMed  Google Scholar 

  46. Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004; 61: 544–555.

    Article  CAS  PubMed  Google Scholar 

  47. Hashimoto R, Straub RE, Weickert CS, Hyde TM, Kleinman JE, Weinberger DR . Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol Psychiatry 2004; 9: 299–307.

    Article  CAS  PubMed  Google Scholar 

  48. Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ et al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 2004; 113: 1353–1363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Neale MC, Eaves LJ, Kendler KS . The power of the classical twin study to resolve variation in threshold traits. Behav Genet 1994; 24: 239–258.

    Article  CAS  PubMed  Google Scholar 

  50. Kotchen TA, Broeckel U, Grim CE, Hamet P, Jacob H, Kaldunski ML et al. Identification of hypertension-related QTLs in African American sib pairs. Hypertension 2002; 40: 634–639.

    Article  CAS  PubMed  Google Scholar 

  51. Martin LJ, Comuzzie AG, Dupont S, Vionnet N, Dina C, Gallina S et al. A quantitative trait locus influencing type 2 diabetes susceptibility maps to a region on 5q in an extended French family. Diabetes 2002; 51: 3568–3572.

    Article  CAS  PubMed  Google Scholar 

  52. Brzustowicz LM, Honer WG, Chow EW, Hogan J, Hodgkinson K, Bassett AS . Use of a quantitative trait to map a locus associated with severity of positive symptoms in familial schizophrenia to chromosome 6p. Am J Hum Genet 1997; 61: 1388–1396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wilcox MA, Faraone SV, Su J, Van Eerdewegh P, Tsuang MT . Genome scan of three quantitative traits in schizophrenia pedigrees. Biol Psychiatry 2002; 52: 847–854.

    Article  CAS  PubMed  Google Scholar 

  54. Weinberger DR . Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660–669.

    Article  CAS  PubMed  Google Scholar 

  55. Woods BT . Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. Am J Psychiatry 1998; 155: 1661–1670.

    Article  CAS  PubMed  Google Scholar 

  56. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B . Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518–526.

    Article  CAS  PubMed  Google Scholar 

  57. Levinson DF, Levinson MD, Segurado R, Lewis CM . Genome scan meta-analysis of schizophrenia and bipolar disorder, part I: Methods and power analysis. Am J Hum Genet 2003; 73: 17–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger Jr JI et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am J Hum Genet 2003; 73: 49–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fanous A, Gardner CO, Prescott CA, Cancro R, Kendler KS . Neuroticism, major depression and gender: a population-based twin study. Psychol Med 2002; 32: 719–728.

    Article  CAS  PubMed  Google Scholar 

  61. McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A . The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497–502.

    Article  PubMed  Google Scholar 

  62. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ . Major depression and generalized anxiety disorder. Same genes, (partly) different environments? Arch Gen Psychiatry 1992; 49: 716–722.

    Article  CAS  PubMed  Google Scholar 

  63. Prescott CA, Aggen SH, Kendler KS . Sex-specific genetic influences on the comorbidity of alcoholism and major depression in a population-based sample of US twins. Arch Gen Psychiatry 2000; 57: 803–811.

    Article  CAS  PubMed  Google Scholar 

  64. Fu Q, Heath AC, Bucholz KK, Nelson E, Goldberg J, Lyons MJ et al. Shared genetic risk of major depression, alcohol dependence, and marijuana dependence: contribution of antisocial personality disorder in men. Arch Gen Psychiatry 2002; 59: 1125–1132.

    Article  PubMed  Google Scholar 

  65. Neale MCCL . Methodology for Genetic Studies of Twins and Families. Dordrecht, Kluwer Academic: The Netherlands, 1992.

    Book  Google Scholar 

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Acknowledgements

This work was supported by NIH Grants MH-41953, MH-52537, MH-45390, and IT-32 MH-20030. AF was supported by an APA/Lilly Psychiatric Research Fellowship and a Young Investigator Award from the American Foundation for Suicide Prevention. We acknowledge the contributions of Michael C Neale, Ph.D., Brien Riley, Ph.D., Xiangning Chen, Ph.D., Todd Webb, Ph.D., Edwin van den Oord, Ph.D., Joseph McClay, Ph.D., Anthony F O’Neill, M.D., Dermot Walsh, MB, FRCPI, and Richard Straub, Ph.D. to unpublished work cited in this paper.

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  1. Washington VA Medical Center, Georgetown University Medical Center Schizophrenia Research Program, Washington, DC, USA

    A H Fanous

  2. Department of Psychiatry, Virginia Commonwealth University, PO Box 980126, Richmond, VA, USA

    A H Fanous & K S Kendler

  3. Department of Human Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA, USA

    K S Kendler

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Fanous, A., Kendler, K. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry 10, 6–13 (2005). https://doi.org/10.1038/sj.mp.4001571

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