MADNESS AND GENETIC DETERMINISM IS MENTAL ILLNESS IN OUR GENES?

HADAMAR PSYCHIATRIC INSTITUTE

Ernst Rüdin Director of the Kaiser Wilhelm Institute for Psychiatry

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

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

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”

“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

Franz Kallmann Visiting Scientist at the Kaiser Wilhelm Institute for Psychiatry

Phillipp Bouhler Chief of the Chancellery

GEKRAT “Charitable Foundation for the Transport of Patients”

Franz Kallmann Professor of Psychiatry at Columbia University

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

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”

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”

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

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

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

Heritability Proportion of variation in a trait due to genetic variation

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

“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

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

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.

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

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

“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.” -- 1965 obituary in the Eugenics Quarterly

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

Nora Iris Myra Hester

National Institute of Mental Health

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

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

“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

“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

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

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

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

The results of the Danish Adoption Study were negative.

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

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

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

Our genes are not our destiny.