I write this in terrible times. Across the world, a pandemic rages nearly unchecked when simple behavioral changes could save many lives. Psychiatric disorders and their sequalae have sharply increased. The role of science, logic, data, and expertise have been pushed to the curb in favor of those who shout loudest

Sullivan P.F

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Psychiatric Genetics Before “Genetics”Patrick F. Sullivan, M.D., F.R.A.N.Z.C.P.for psychotic disorders; inheritance is probabilistic, not de-terministic; inheritance affects risk for a class of psychiatricdisorders rather than one type; and risk blends into normalpersonality and behavior.All of these features are supported in the current litera-ture. Crucially, the findings noted by Kendler have beenextended with direct measurements of DNA variation atgenome scale in large samples from across the world. DNAfindings are augmented with information from functionalstudies of the human brain (increasingly at the single-celllevel). As touchstones for the interested reader, various pa-pers may be found that describe current knowledge of thegenetic architectures of psychiatric disorders (2), the state-of-the-science for schizophrenia (the most advanced form ofinsanity) (3–5) and autism (6), topical reviews of all majordisorders (7), the overlap of genetic risk between differentpsychiatric disorders (8), connections to brain cell types (9,10), and the clinical implications (11). One of the empiricaltriumphs of the past decade is the vast increase in secureempirical knowledge: we are getting at the ground truths forpsychiatric disorders, afoundation that we havenever had before.All papers have limi-tations. As an active re-searcher in psychiatricgenomics, did Kendlerproject his “presentism”onto these texts?Do thesetexts reflect fewer unique perspectives—was there a greatprofessor or twowhose opinions are common to all accounts?These seem unlikely, as so many different authors expressedsimilar ideas over time (130 years), geography (from theUnited States to Austria), and competing intellectual tradi-tions. The detail provided in the article’s tables serve to di-minish these concerns. To expand out from Europeanthought, my hope is that someone reading this will help usunderstand thinking about genetics and insanity from non-European traditions (e.g., the great physicians from Islam,China, and India).As noted in Kendler’s introduction, many date “real ge-netics” to Mendel, Galton, Fisher, and Pearson around acentury ago (for thatmatter, some think that paperswithout aPDFor absent from theirTwitter feed arenotworth reading).This careful review demonstrates that core genetic conceptswere widely appreciated long before any of this. For thatThese observant andthoughtful clinicians from110-plus years ago mostlygot it right. Kendler’s coreconclusions from his reviewparallel modern findings.I write this in terrible times. Across the world, a pandemic rages nearly unchecked when simple behavioral changes could save many lives. Psychiatric disorders and their sequalae have sharply increased. The role of science, logic, data, and expertise have been pushed to the curb in favor of those who shout loudest.In this context—especially in this context—it is a delight and a comfort to read and comment on Prof. Kendler’s latest scholarly work, in this issue of the Journal (1), on what ob-servant early European and American psychiatrists made of the tendency of severe mental illnesses to run in families: delight from the craft, care, and scholarship that comprise (and typify) Kendler’s contributions, and comfort from the echo of clinical inferences drawn by our predecessors cen-turies ago in the empirical data we have today. After defining a few terms, one can imagine an interesting conversation with these clinicians. (A further comfort is the reminder that human history has always been tough—war, pandemic, genocide, enslavement, persecution, famine, threat, and uncertainty; they got through it, and so will we.)Kendler has long been devoted to the historical and philosophical basis of psychiatry and, particularly, genetic approaches. In this new work, he identifies and reviews 48 texts from the late Holocene. It is always tricky to place boundaries on continua, but the choice of starting with the work of Cullen (1780) and continuing through that of Rüdin and Rosanoff (just before World War I) constitutes a de-fensible set of bookends. Notably, these works were blind to fundamental genetic facts (DNA, chromosomes, principles of inheritance) as well as to all the careful empiricism of psy-chiatric epidemiology, genetic epidemiology, and genetics that inform us today.And yet these observant and thoughtful clinicians from 110-plus years ago mostly got it right. Kendler’s core con-clusions from his review parallel modern findings. It seems reasonable to assume that “insanity” translates to modern diagnostic entities—idiopathic syndromes with prominent, persistent, and pervasive psychotic symptoms like schizo-phrenia, schizoaffective disorder, or a mood disorder with psychotic features—and assuming that there are relatively small proportions of people with some other psychiatric disorder confusable with “insanity” (e.g., autism, obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, severe alcoholism) or a general medical cause (pellagra, neurosyphilis, etc.). There are precise parallels in the top-level conclusions: family history is a strong risk factorAm J Psychiatry 2021; doi: 10.1176/appi.ajp.2021.21020136REFERENCES1. Kendler KS: The prehistory of psychiatric genetics: 1780–1910. Am JPsychiatry 2021; 178:490–5082. Sullivan PF, Geschwind DH: Defining the genetic, genomic, cellular,and diagnostic architectures of psychiatric disorders. Cell 2019; 177:162–1833. Singh TJ, Neale BM, Daly MJ: Exome sequencing identifies rare codingvariants in 10 genes which confer substantial risk for schizophrenia.medRxiv,September18,2020(https://doi.org/10.1101/2020.09.18.20192815)4. SchizophreniaWorkingGroupofPsychiatricGenomicsConsortium:Mapping genomic loci prioritises genes and implicates synaptic bi-ology in schizophrenia. medRxiv, September 13, 2020 (https://doi.org/10.1101/2020.09.12.20192922)5. Marshall CR, Howrigan DP, Merico D, et al: Contribution of copynumber variants to schizophrenia from a genome-wide study of41,321 subjects. Nat Genet 2017; 49:27–356. Satterstrom FK, Kosmicki JA, Wang J, et al: Large-scale exomesequencing study implicates both developmental and functionalchanges in the neurobiology of autism. Cell 2020; 180:568–584.e5237. Sullivan PF, Kendler KS: The state of the science in psychiatricgenomics. Psychol Med 2021; 1–38. Brainstorm Consortium, Anttila V, Bulik-Sullivan BK, et al: Analysisof sharedheritability in commondisordersof thebrain. Science2018;360:eaap87579. Skene NG, Bryois J, Bakken TE, et al: Genetic identification of braincell types underlying schizophrenia. Nat Genet 2018; 50:825–83310. Bryois J, Skene NG, Hansen TF, et al: Genetic identification of celltypes underlyingbrain complex traits yields insights into the etiologyof Parkinson’s disease. Nat Genet 2020; 52:482–49311. SullivanPF,OwenMJ: Increasing the clinical psychiatric knowledgebase about pathogenic copynumbervariation.AmJPsychiatry 2020;177:204–20912. Finucane HK, Bulik-Sullivan BK, Gusev A, et al: Partitioning heri-tability by functional annotation using genome-wide associationsummary statistics. Nat Genet 2015; 47:1228–123513. Zoonomia C; Zoonomia Consortium: A comparative genomicsmultitool for scientificdiscoveryandconservation.Nature2020; 587:240–245matter, humans have been doing practical genetics for mil-lennia, such as when we (repeatedly) domesticated wolves and horses and improved maize and grain via thoughtful observation and practical experimentation. In fact, it is more pervasive, deeper, and far older than any of this: our genomes and risks for severe psychiatric disorders are still deeply affected by hundreds of millions of years of mammalian evolution (12, 13).AUTHOR AND ARTICLE INFORMATIONUniversity of North Carolina, Departments of Genetics and Psychiatry, Chapel Hill; Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm.Send correspondence to Dr. Sullivan (pfsulliv@med.unc.edu).Supported by the Swedish Research Council (Vetenskapsrådet, award D0886501) and NIMH grants MH077139 and MH1095320.Dr. Sullivan has received grant support from and served on an advisory committee for Lundbeck and has served on an advisory committee and is a shareholder in RBNC Therapeutics.Accepted February 4, 2021.178: 75– 76;44

Psychiatric Genetics Before "Genetics"

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