Manfred Bleuler’s letter to Robert H. Belmaker

Bernard Lerer’s comment


        Haim Belmaker quotes Bleuler's belief that "schizophrenia would never be found to have a single gene as a cause, since… genes act on behavior via temperament, and inheritance of conflicting temperaments causes a personality breakdown that constitutes schizophrenia." I recall Haim strongly expressing this view over many years. He was certainly correct about there not being common, single genes for the major psychiatric disorders. However, there may well be rare loci of major effect. In this regard, a recent whole genome sequencing paper published in Molecular Psychiatry with my collaborator, David Goldstein of Columbia University, and my former PhD student and postdoc, Anna Alkelai, as the first author, found interesting leads in well characterized family samples (Alkelai, Greenbaum, Docherty et al. 2021).

        In fairness to the field, the naive belief in finding single major genes for psychiatric disorders such as schizophrenia and bipolar disorder did not last very long and was abandoned after the first wave of linkage studies came up with nothing. On the other hand, rare variants of major effect have been found in several disorders. A key example is autism where a number of rare genetic variants have indeed been discovered (Kanani Study and Balasubramanian 2018). See also an intriguing recent paper from the Birk group at Ben Gurion University in Beersheba, Israel (to which my lab contributed the behavioral phenotyping in mice) showing a single major variant associated with ADHD in a consanguineous Bedouin family (Halperin, Stavsky, Kadir et al. 2021).

        A key focus of the psychiatric genetic community is on trying to make something out of the multiple variants of small influence that have been discovered for schizophrenia, bipolar and other disorders using polygenic risk scores. It is still not clear what will emerge from this for psychiatric disorders but there is evidence for potential clinical utility (Lambert, Abraham and Inouye 2019).

        To my knowledge there is no empirical support for the postulate that multiple small genes are involved in the causation of major psychiatric disorders via temperament and that "inheritance of conflicting temperaments causes a personality breakdown that constitutes schizophrenia." There is extensive evidence that multiple genes of small effect are associated with susceptibility to schizophrenia. I also have no doubt that multiple genes of small effect contribute to temperament. The second part of the hypothesis awaits supporting evidence.



Alkelai A, Greenbaum L, Docherty AR, Shabalin AA, Povysil G, Malakar A, Hughes D, Delaney SL, Peabody EP, McNamara J, Gelfman S, Baugh EH, Zoghbi AW, Harms MB, Hwang HS, Grossman-Jonish A, Aggarwal V, Heinzen EL, Jobanputra V, Pulver AE, Lerer B, Goldstein DB. The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders. Mol Psychiatry 2021.

Halperin D, Stavsky A, Kadir R, Drabkin M, Wormser O, Yogev Y, Dolgin V, Proskorovski-Ohayon R, Perez Y, Nudelman H, Stoler O, Rotblat B, Lifschytz T, Lotan A, Meiri G, Gitler D, Birk OS. CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice. Nat Commun. 2021;12(1):6187

Kanani F, Study D, Balasubramanian M. SHANK3 variant as a cause of nonsyndromal autism in an 11-year-old boy and a review of published literature. Clin Dysmorphol. 2018;27(4):113-115.

Lambert SA, Abraham G, Inouye M. Towards clinical utility of polygenic risk scores. Hum Mol Genet. 2019;28(R2):R133-R142.


April 14, 2022