Institute for Response-Genetics (e.V.)

Chairman: Prof. Dr. Hans H. Stassen

Psychiatric Hospital (KPPP), University of Zurich

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Diagnoses-crossing Vulnerability

Epidemiologic data indicate that overweight and obesity are on the rise worldwide. Psychiatric patients are particularly vulnerable in this respect as they have an increased prevalence of overweight and obesity, and often experience rapid, highly undesirable weight gain under psychotropic drug treatment. Current treatment strategies in psychiatry are oriented towards polypharmacy, so that the information on drug-induced weight gain from earlier monotherapy studies is of very limited validity.

Clinical Study

To analyze the extent to which irregularities in genetic diversity might separate psychiatric patients from healthy controls we have carried out a study of 1,431 patients and 267 healthy controls. The subjects were genotyped for 100 genes and 549 specifically selected SNPs at a missing data rate <5%. Of the healthy controls, 141 (52.8%) were unaffected 1st degree relatives of the patients. The patients had been recruited from the daily admissions at mental health treatment centers in Germany and Switzerland. Selection criterion was a suspected ICD-10 diagnosis of F20 (schizophrenia), F25 (schizoaffective disorders), F31 (bipolar illness), or F32/F33 (major depression). Genetic diversity was quantified through multidimensional "gene vectors" assembled from 4-8 polymorphic SNPs located within each of 100 candidate genes. The number of different genotypic patterns observed per gene was called the gene’s “diversity index”.

Singular Genes

The diversity indices were found to be only weakly correlated with their constituent number of SNPs (20.5% explained variance), thus suggesting that genetic diversity is an intrinsic gene property that has evolved over the course of evolution. Significant deviations from "normal" diversity values were found for (1) major depression; (2) Alzheimer’s disease; and (3) schizoaffective disorders. Almost one third of the genes were correlated with each other, with correlations ranging from 0.0303 to 0.7245.

The central finding of this study was the discovery of "singular genes" characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls. Multilayer Neural Nets yielded nonlinear classifiers that correctly identified up to 90% of patients. Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities.

Detailed analyses of the variation of genotypic patterns in genes along with the correlation between genes lead to nonlinear classifiers that enable very robust separation between psychiatric patients and healthy controls on the genotype level. [get the article].

References

Stassen HH, Bachmann S, Bridler R, Cattapan K, Seifritz E. Polypharmacy in Psychiatry and Weight Gain: Longitudinal Study of 832 Patients Hospitalized for Depression or Schizophrenia, along with Data of 3,180 Students from Europe, the U.S., South America, and China. Eur Arch Psychiatry Clin Neurosci. 2024; https://doi.org/10.1007/s00406-024-01767-2 (Epub ahead of print) [get the article]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C: Genetic Determinants of Antidepressant and Antipsychotic Drug Response: A molecular-genetic study of 902 patients over 6 weeks. Eur Arch Psychiatry Clin Neurosci. 2024. doi: 10.1007/s00406-024-01918-5 (Epub ahead of print) [get the article]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C. Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs). Psychiatry Res. 2024; 333: 115720. doi: 10.1016/j.psychres.2024.115720 [get the article]
Greil W, de Bardeci M, Müller-Oerlinghausen B, Nievergelt N, Stassen HH, Hasler G, Erfurth A, Cattapan K, Rüther E, Seifert J, Toto S, Bleich S, Schoretsanitis G. Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data. Int J Bipolar Disord. 2023; 11(1): 34. doi: 10.1186/s40345-023-00313-8 [get the article]
de Bardeci M, Greil W, Stassen H, Willms J, Köberle U, Bridler R, Hasler G, Kasper S, Rüther E, Bleich S, Toto S, Grohmann R, Seifert J. Dear Doctor Letters regarding citalopram and escitalopram: guidelines vs real-world data. Eur Arch Psychiatry Clin Neurosci. 2023; 273(1): 65-74 [get the article]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Schneeberger A, Seifritz E: Detailing the Effects of Polypharmacy in Psychiatry: Longitudinal Study of 320 Patients Hospitalized for Depression or Schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2022; 272(4): 603-619 [get the article]
Greil W, de Bardeci M, Seifert J, Bernegger X, Cattapan K, Stassen HH, Wagner AL, Sieberer M, Grohmann R, Toto S: Treatment of depression: Are psychotropic drugs appropriately dosed in women and in the elderly? Dosages of psychotropic drugs by sex and age in routine clinical practice. Hum Psychopharmacol. 2022; 37(1): e2809 [get the article]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Schneeberger A, Seifritz E: Inflammatory Processes linked to Major Depression & Schizophrenic Disorders and the Effects of Polypharmacy in Psychiatry: Evidence from a longitudinal Study of 279 Patients under Therapy. Eur Arch Psychiatry Clin Neurosci. 2021; 271(3): 507-520 [get the article]
Pollak TA, Lennox B, Müller S, Benros ME, Prüss H, Tebartz van Elst L, Klein H, Steiner J, Frodl T, Bogerts B, Tian L, Groc L, Hasan A, Baune BT, Endres D, Haroon E, Yolken R, Benedetti F, Halaris A, Meyer J, Stassen HH, Leboyer M, Fuchs D, Otto M, Brown DA, Vincent A, Najjar S, Bechter K: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin: the concept of autoimmune psychosis. Lancet Psychiatry 2020; 7(1): 93-108
Zhang M, Bridler R, Mohr C, Moragrega I, Sun N, Xu Z, Yang Z, Possenti M, Stassen HH: Early Detection of the Risk of Developing Psychiatric Disorders: A Study of 461 Chinese University Students under Chronic Stress. Psychopathology 2019; 52(6): 367-377 [get the article]
Bhake R, Kluckner V, Stassen HH, Russell GM, Leendertz J, Stevens K, Linthorst ACE, Lightman S: Continuous Free Cortisol Profiles – Circadian Rhythms in Healthy Men. J Clinical Endocrinology & Metabolism 2019; 104(12): 5935-5947
Stassen HH: Heterogeneity of schizophrenic disorders and link to chronically elevated IgM values. Neurology, psychiatry and brain research 2018; 29: 23-24
Braun S, Bridler R, Müller N, Schwarz MJ, Seifritz E, Weisbrod M, Zgraggen A, Stassen HH: Inflammatory Processes and Schizophrenia: Two Independent Lines of Evidence from a Study of Twins Discordant and Concordant for Schizophrenic Disorders. Eur Arch Psychiatry Clin Neurosci 2017; 267: 377-389 [get the article]
Stassen HH, Delfino JP, Kluckner VJ, Lott P, Mohr C: Vulnerabilität und psychische Erkrankung. Swiss Archives of Neurology and Psychiatry 2014; 165(5): 152-157
Drago A, Giegling I, Schäfer M, Hartmann AM, Friedl M, Konte B, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: AKAP13, CACNA1, GRIK4 and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment. Eur Neuropsychopharmacol. 2013; 23(8): 887-894
Giegling I, Balzarro B, Porcelli S, Schäfer M, Hartmann AM, Friedl M, Konte B, Krämer P, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol. Eur Arch Psychiatry Clin Neurosci. 2013; 263(1): 65-74
Drago A, Giegling I, Schäfer M, Hartmann AM, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: No association of a set of candidate genes on haloperidol side effects. PLoS One. 2012; 7(10): e44853
Giegling I, Drago A, Schäfer M, Hartmann AM, Sander T, Toliat MR, Möller HJ, De Ronchi D, Stassen HH, Rujescu D, Serretti A: Lack of association between 71 variations located in candidate genes and response to acute haloperidol treatment. Psychopharmacology 2011; 214(3): 719-728
Giegling I, Drago A, Dolzan V, Plesnicar BK, Schäfer M, Hartmann AM, Sander T, Toliat MR, Möller HJ, Stassen HH, Rujescu D, Serretti A: Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. Pharmacogenet Genomics. 2011; 21(4): 206-216
Gravemann S, Schnipper N, Meyer H, Vaya A, Nowaczyk MJM, Rajab A, Hofmann WK, Salewsky B, Tönnies H, Neitzel H, Stassen HH, Sperling K, Hoffmann K: Dosage effect of zero to three functional LBR-genes in vivo and in vitro. Nucleus 2010; 1(2): 1-12
Hoffmann K, Planitz C, Rüschendorf F, Müller-Myhsok B, Stassen HH, Lucke B, Mattheisen M, Stumvoll M, Bochmann R, Zschornack G, Wienker TF, Nürnberg P, Reis A, Luft FC, Lindner TH: A novel locus for arterial hypertension on chromosome 1p36 maps to a metabolic syndrome trait cluster in the Sorbs, a Slavic population isolate in Germany. J Hypertens 2009; 27: 983-990
Stassen HH, Hoffmann K, Scharfetter C: The Difficulties of Reproducing Conventionally Derived Results through 500k-Chip Technology. BMC Genet Proc. 2009; 3 Suppl 7: S66
Tadic A, Rujescu D, Dahmen N, Stassen HH, Muller MJ, Kohnen R, Szegedi A: Association Analysis between Variants of the Interleukin-1? and the Interleukin-1 Receptor Antagonist Gene and Antidepressant Treatment Response in Major Depression. Neuropsychiatr Dis Treat 2008; 4(1): 269-276
Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A: Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2'848 patients. J Clin Psychiatry 2007; 68(8): 1195-1205
Tadic A, Rujescu D, Müller MJ, Kohnen R, Stassen HH, Dahmen N, Szegedi A: A monoamine oxidase B gene variant and short-term antidepressant treatment response. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(7): 1370-1377
Tadic A, Müller MJ, Rujescu D, Kohnen R, Stassen HH, Dahmen N, Szegedi A: The MAOA T941G polymorphism and short-term treatment response to mirtazapine and paroxetine in major depression. Am J Med Genet B Neuropsychiatr Genet. 2007; 144(3): 325-331
Stassen HH, Szegedi A, Scharfetter C: Modeling Activation of Inflammatory Response System. A Molecular-Genetic Neural Network Analysis. BMC Proceedings 2007, 1 (Suppl 1): S61, 1-6
Berger M, Stassen HH, Köhler K, Krane V, Mönks D, Wanner C, Hoffmann K, Hoffmann MM, Zimmer M, Bickeböller H, Lindner TH: Hidden population substructures in an apparently homogeneous population bias association studies. Eur J Hum Genetics 2006; 14: 236-244
Stassen HH, Angst J, Scharfetter C, Szegedi A: Therapie mit Antidepressiva: Erfolg von genetischen Faktoren abhängig? Leading Opinions, Neurologie & Psychiatrie 2005; 6: 25-27
Szegedi A, Rujescu D, Tadic A, Müller MJ, Ralf Kohnen R, Stassen HH, Dahmen N: The catechol-O-methyltransferase Val108/158Met-polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in Major Depression. Pharmacogenomics 2005; 5(1): 49-53
Stassen HH, Bridler R, Hell D, Weisbrod M, Scharfetter C: Ethnicity-independent genetic basis of functional psychoses. A Genotype-to-phenotype approach. Am J Med Genetics B 2004; 124: 101-112
Stassen HH, Hoffmann K, Scharfetter C: Similarity by state/descent and genetic vector spaces: Analysis of a longitudinal family study. Genetic Analysis Workshop 13: Analysis of longitudinal family data for complex diseases and related risk factors. BMC Genet 2003; 4, S59: 1-6
Stassen HH, Scharfetter C: Oligogenic approaches to the predisposition of asthma in ethnically diverse populations. Genetic Analysis Workshop 12: Analysis of genetic and environmental factors in common diseases. Genetic Epidemiology 2001; 21(1): 284-289
Hoffmann K, Stassen HH, Reis A: Genkartierung in Isolatpopulationen. Medizinische Genetik 2000; 12,4: 428-437
Stassen HH, Bridler R, Hägele S, Hergersberg M, Mehmann B, Schinzel A, Weisbrod M, Scharfetter C: Schizophrenia and smoking: evidence for a common neurobiological basis? Am J Med Genetics B 2000; 96: 173-177
Stassen HH and Scharfetter C: Integration of genetic maps by polynomial transformations. Am J Med Genetics B 2000; 96: 108-113
Stassen HH, Begleiter H, Porjesz B, Rice J, Scharfetter C, Reich T: Structural decomposition of genetic diversity in families with alcohol dependence. Genetic Analysis Workshop 11: Analysis of genetic and environmental factors in common diseases. Genetic Epidemiology 1999; 17: 325-330

 

vSpacer Distribution of the diversity indices of 100 genes as observed in 1,698 Central European subjects
Distribution of the diversity indices of 100 genes as observed in 1,698 Central European subjects (including a small number of U.S. Americans). The diversity index ranged from 18 (CYP2C19) to 476 (GPR39) with a mean value of 109.4±82.8. The distribution revealed two peaks (diversity indices around 70 and 170), along with 7 genes exhibiting a diversity index above 250. These results may indicate different types of genes.
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