1. MADNESS AND GENETIC DETERMINISM
IS MENTAL ILLNESS IN OUR GENES?

2. HADAMAR PSYCHIATRIC INSTITUTE

3. Ernst Rüdin
Director of the Kaiser Wilhelm Institute for Psychiatry

4. Outline of Psychiatric Genetics
I. “Classical” Genetics
A. Family Studies
B. Twin Studies
C. Adoption Studies
II. Molecular Genetics
A. Linkage Studies
B. Candidate Gene Studies
C. Genome-Wide Association Studies

5. Career of Ernst Rüdin
1909: Succeeds Alois Alzheimer as Senior Physician of Munich Hospital 1918: Appointed Director of Genealogical and Demographic Studies at the German Institute for Psychiatric Research (later re-named the Kaiser Wilhelm Institute) 1931: Appointed Director of the Kaiser Wilhelm Institute

6. 30 January 1933: Hitler becomes Chancellor of the Reich
3 June 1933: Rüdin appointed to Standing Committee for Racial
Hygiene
Authors law mandating sterilization of “undesirables”

7. “Undesirables” A category that included:
Congenital mental defects
Schizophrenia
Manic-depressive psychosis
Hereditary epilepsy
Hereditary chorea
Hereditary blindness
Hereditary deafness
Severe physical deformity
Severe alcoholism

8. Franz Kallmann
Visiting Scientist at the Kaiser Wilhelm Institute for Psychiatry

9. Phillipp Bouhler
Chief of the Chancellery

10. GEKRAT “Charitable Foundation for the Transport of Patients”

11. Franz Kallmann
Professor of Psychiatry at Columbia University

12. “Schizoid personalities”
I. Schizoid eccentrics and borderline cases II. Schizoid psychopaths

13. Schizoid eccentrics and borderline cases
“Cranks and eccentrics, stubborn and perverse recalcitrants, malicious and cold-hearted despots, superstitious and pietistic religio-maniacs, secretive reclusives, sectarian dreamers out of touch with reality, and the over-pedantic, avaricious and literal-minded people”

14. Schizoid psychopaths
“Unsociable, cold-hearted, indecisive and fanatic types, bullheaded oafs, malicious tyrants, queer cranks, over-pedantic schemers, prudish ‘model children’ and daydreamers out of all touch with reality”

15. The central assumption underlying family studies – that familial equals genetic – is false.

16. Types of Twins
Monozygotic (MZ) or Identical Twins: 100% similarity in genes identical by descent Dizygotic (DZ) or Fraternal Twins: 50% similarity in genes identical by descent

17. Concordance Rate
Percentage of twin pairs in which both members share the trait ÷ Percentage of twin pairs in which at least one member shares the trait

18. Heritability
Proportion of variation in a trait due to genetic variation

19. Equal Environment Assumption
The environment experienced by identical (MZ) twin pairs is, on average, no more similar than that experienced by fraternal (DZ) twin pairs

20. “As soon as we shall be able to duplicate or sufficiently reinforce the heredoconstitutional mechanisms responsible for a satisfactory resistance to the disintegrating effects of a schizophrenic process, the therapeutic problem of schizophrenia will be nearer its final solution.”
-- Kallmann and Barrera 1942

21. Kallmann (1946) 174 DZ twin pairs 517 MZ twin pairs
Concordance rate for schizophrenia:
DZ Twins: 15%
MZ Twins: 86%

22. No other study has come close to replicating Kallmann’s reported 86% concordance rate. No study performed after 1962 has reported a concordance rate even as high as 25%. When one member of a pair of identical twins is diagnosed with schizophrenia, odds are better than three out of four that the other will not be.

23. The central assumption underlying twin studies – the Equal Environment Assumption – is false.

24. “Psychiatric eugenics appears to be safely on the march.”
-- Franz Kallmann, January 1945

25. “The distinguished career of Dr. Franz J
“The distinguished career of Dr. Franz J. Kallmann as a researcher and teacher came to a close with his death on May 12. His contributions to the field of human genetics were established with his classic work on the genetics of schizophrenia. By 1936 his opposition to Nazi laws requiring compulsory sterilization of mentally ill patients had made his position in his native Germany scientifically untenable. Coming to the United States, he almost single-handedly founded the discipline of psychiatric genetics in this country.”
obituary in the Eugenics Quarterly

26. The Genain Quadruplets
The name “Genain” is derived from the Greek words genos and ainos and literally means “Dire Birth.”

27. Nora Iris Myra Hester

28. National Institute of Mental Health

29. The Danish Adoption Study
76 Index cases
Birth mother diagnosed with schizophrenia
67 controls
Matched to index cases in terms of sex, age, socioeconomic status of adoptive parents, and time spent with biological family

30. The Danish Adoption Study found no correlation between a diagnosis of schizophrenia and having a schizophrenic birth mother.

31. “Schizophreniform Disorders”
schizophrenic-like border cases
borderline schizophrenia
paranoid borderline
psychotic borderline
close to borderline psychotic
conceivably paranoid borderline
schizophrenic diathesis (with some doubt)
pronounced prepsychotic features
suspicion of organic brain syndrome
schizoid: beginning schizophrenia?
moderately schizoid

32. “If we had relied on only hard-core, process cases, we would have found no significant difference between our index and control cases.”
-- David Rosenthal, 1972

33. 1974: Rate of “schizophreniform disorders” higher among index adoptees 1978: No difference between index cases and controls in the rate of “schizophreniform disorders”

34. Some of the “interviews” never took place
Other “interviews” consisted of a five-minute doorstep conversation

35. The adoptive families of the index cases and the control cases were not comparable.

36. The results of the Danish Adoption Study were negative.

37. The central premise of adoption studies – that adoption serves to randomize environmental variation – is false.

38. Genome-Wide Association Studies
DNA of index subjects scanned for single-nucleotide polymorphisms (SNP’s) and compared to that of controls Sample sizes on the order of 104 or greater Significance levels normally set at p = 10-8

39. Schizophrenia Working Group of the Psychiatric Genetics Consortium
Scanned the DNA of 36,989 index subjects and 113,075 controls
108 loci associated with schizophrenia
Odds ratios of 1.2 or less
Equivalent to an absolute increase in risk of one in five hundred, or even less

40. Our genes are not our destiny.