Publications by authors named "Kenneth S Kendler"

696 Publications

The impact of sex, age at onset, recurrence, mode of ascertainment and medical complications on the family genetic risk score profiles for alcohol use disorder.

Psychol Med 2021 Oct 8:1-9. Epub 2021 Oct 8.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Alcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment.

Methods: In the Swedish population born 1932-1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants.

Results: FGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders.

Conclusions: From a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.
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http://dx.doi.org/10.1017/S0033291721003317DOI Listing
October 2021

The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study.

JAMA Psychiatry 2021 Sep 29. Epub 2021 Sep 29.

23andme, Inc, Sunnyvale, California.

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations.

Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression.

Design, Setting, And Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021.

Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts.

Main Outcomes And Measures: Depression status was defined based on health records and self-report questionnaires.

Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent.

Conclusions And Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.2099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482304PMC
September 2021

The Debate Between Two of the Founders of American Psychiatric Genetics, Aaron Rosanoff and Abraham Myerson, on Mendelian Models for Psychiatric Illness: 1911-1917.

J Nerv Ment Dis 2021 Sep 14. Epub 2021 Sep 14.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia.

Abstract: In 1911, Aaron Rosanoff published among the first pedigree studies of psychiatric illness, and the first ever in the United States, claiming that the neuropathic constitution was transmitted in as a Mendelian recessive disorder. In 1917, Abraham Myerson harshly critiqued that study, focusing on the very wide phenotypic definition of neuropathic constitution. Here, I describe Rosanoff and Myerson's backgrounds, the details of Rosanoff's study, and Myerson's critique and put this controversy in the context of the history of psychiatric genetics, emphasizing four themes: a) the close interrelationship between psychiatric diagnosis and models of genetic transmission, b) the strong attraction of Mendelian models to psychiatric geneticists after their 1900 rediscovery, c) the controversy about whether familial transmission of psychiatric illness is largely homogeneous or heterogeneous, and d) the methods taken by researchers to the problems of psychiatric genetics that typically emerged as part of their broader approach to the nature of psychiatric illness.
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http://dx.doi.org/10.1097/NMD.0000000000001419DOI Listing
September 2021

Ernst Rüdin's, 1911 vision of a Mendelian psychiatric genetics research program: His paper "Methods and goals of family research in psychiatry".

Am J Med Genet B Neuropsychiatr Genet 2021 07 20;186(5):279-288. Epub 2021 Aug 20.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia, USA.

While working under Kraepelin in Munich, Ernst Rüdin, a Swiss-born Psychiatrist, at the age of 26, outlined in a 1911 98-page article, a detailed plan for a future Mendelian-informed family research program for psychiatry. Rüdin would go on to head the Department of Genealogical and Demographic Studies at Kraepelin's Research Institute which became one of the world's leading programs in psychiatric genetics. I here summarize this article, providing a complete translation online. Rüdin's review outlined a paradigm shift in psychiatric genetics research moving from calculations of aggregate hereditary burden, as they applied to the proband, to examining patterns of transmission within family pedigrees which involved careful individual assessments of relatives. He references widely clinical and statistical genetic studies, many focusing on the newly discovered Mendelian laws. However, Rüdin was no genetic reductionist but recognized the contribution of environmental risk factors to psychiatric illness arguing that they should be studied as part of a comprehensive research program. As a committed eugenicist, Rüdin also explored the implications of such a program for "racial hygiene." Rüdin's contributions should be viewed in the context of his extensive collaboration from 1933 to 1945 with the National Socialists and his support for their eugenics program, including involuntary sterilizations.
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http://dx.doi.org/10.1002/ajmg.b.32870DOI Listing
July 2021

"Manifestations of insanity": Kraepelin's final views on psychiatric nosology in their historical context.

Mol Psychiatry 2021 Aug 2. Epub 2021 Aug 2.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA, USA.

Emil Kraepelin, more than any other individual, has shaped the nature of our psychiatric diagnostic system. Kraepelin published his final contribution to psychiatric nosology as an essay in 1920, which both modified and explicated the conceptual foundation for this approach to diagnosis. This essay was a response to a new generation of psychiatrists, particularly Karl Jaspers, Karl Birnbaum, and Ernst Kretschmer, who each challenged Kraepelin's view that psychiatric disorders represent natural kinds, (i.e., truly distinct entities). They had argued for a structural analysis of psychosis stressing the impact of unique, personal attributes on the causes and clinical presentations of mental diseases. The authors give this text a close reading and conclude that it offers a final nuanced description of Kraepelin's advanced nosologic views and his emerging interest in life history and culture. Kraepelin held fast to his position that psychiatric disorders represented distinct natural kinds, but acknowledged that the distinctions between them were often obscured by personality, life experiences, and/or cultural effects. Kraepelin used several metaphors to illustrate his final views, that of an "organ register" being the most prominent. Psychiatric disorders, he postulated, belong to three registers, each with its own distinct clinical features and putative brain-based mechanisms. Published a century ago, this final synthesis of Kraepelin's views, a capstone to his career, raises central issues about the nature of psychiatric illness and the appropriate goals for psychiatric nosology. They are fertile issues for psychiatric research and practice today.
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http://dx.doi.org/10.1038/s41380-021-01232-9DOI Listing
August 2021

Prosper Lucas and his 1850 "Philosophical and Physiological Treatise on Natural Heredity".

Am J Med Genet B Neuropsychiatr Genet 2021 07 15;186(5):261-269. Epub 2021 Jul 15.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia, USA.

Prosper Lucas (1808-1885) is a unique figure in the history of psychiatric genetics. A physician-alienist, he authored one of the most important books on human genetics in the mid-19th century cited frequently by Darwin: the 1,500 page treatise-Philosophical and Physiological Treatise on Natural Heredity (1847-1850). This book contained a novel theory of the nature of inheritance and a detailed review of the heredity of a range of human traits and disorders, including various forms of insanity. Lucas postulated four forms of heredity (direct, crossed, indirect, and atavistic), supported the importance of hereditary factors in insanity, accepted the inheritance of acquired characteristics, considered it important to examine both ancestors and collateral relatives, and recognized that heredity could influence both primary insanity and insanity secondary to other medical conditions. He reviewed the then available literature on most major forms of insanity including separate sections on hallucinations and suicidal monomania. The literature consisted of case reports of unusual families with high concentrations of illness. Lucas advocated for the homogeneity of transmission of forms of illness in families but recognized that-just as the form of illness could evolve within individuals over time-it could change forms when transmitted between relatives.
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http://dx.doi.org/10.1002/ajmg.b.32867DOI Listing
July 2021

Prosper Lucas and his 1850 "Philosophical and Physiological Treatise on Natural Heredity".

Am J Med Genet B Neuropsychiatr Genet 2021 07 15;186(5):261-269. Epub 2021 Jul 15.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia, USA.

Prosper Lucas (1808-1885) is a unique figure in the history of psychiatric genetics. A physician-alienist, he authored one of the most important books on human genetics in the mid-19th century cited frequently by Darwin: the 1,500 page treatise-Philosophical and Physiological Treatise on Natural Heredity (1847-1850). This book contained a novel theory of the nature of inheritance and a detailed review of the heredity of a range of human traits and disorders, including various forms of insanity. Lucas postulated four forms of heredity (direct, crossed, indirect, and atavistic), supported the importance of hereditary factors in insanity, accepted the inheritance of acquired characteristics, considered it important to examine both ancestors and collateral relatives, and recognized that heredity could influence both primary insanity and insanity secondary to other medical conditions. He reviewed the then available literature on most major forms of insanity including separate sections on hallucinations and suicidal monomania. The literature consisted of case reports of unusual families with high concentrations of illness. Lucas advocated for the homogeneity of transmission of forms of illness in families but recognized that-just as the form of illness could evolve within individuals over time-it could change forms when transmitted between relatives.
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http://dx.doi.org/10.1002/ajmg.b.32867DOI Listing
July 2021

The nature of hereditary influences on insanity from research on asylum records in Western Europe in the mid-19th century.

Am J Med Genet B Neuropsychiatr Genet 2021 07 6;186(5):270-278. Epub 2021 Jul 6.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia, USA.

This article explores the nature of psychiatric genetics research conducted in asylums in Western Europe in the mid-19th century through an examination of four studies published 1841 to 1864 from Great Britain, France, and Germany. They all utilize asylum records to determine if patients had a hereditary predisposition (HP) to mental illness. A diverse range of topics were investigated, with most attention on whether men or women are more likely to transmit, or are more sensitive to the receipt of, an HP. When significant sex effects were seen, they consistently found women to be more likely to transmit and/or more sensitive to the receipt of an HP. Other questions explored included: (a) the relationship between an HP and recurrence rates; (b) the degree of homogeneity versus heterogeneity of transmission of specific mental illnesses in families; (c) the level of HP among different forms of mental illness; and (d) differences in the proportion of psychiatric patients with an HP as a function of their religion. While the method of assessment of familial/genetic risk was relatively crude, even at this early stage in the history of psychiatric genetics, investigators were asking thoughtful questions about the nature and clinical impact of that risk.
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http://dx.doi.org/10.1002/ajmg.b.32865DOI Listing
July 2021

Drinking cultures and socioeconomic risk factors for alcohol and drug use disorders among first- and second-generation immigrants: A longitudinal analysis of Swedish population data.

Drug Alcohol Depend 2021 09 18;226:108804. Epub 2021 Jun 18.

Alcohol Research Group, Public Health Institute, Emeryville, CA, USA; Community Health and Implementation Research Program, RTI International, Berkeley, CA, USA.

Background: Few longitudinal studies investigate predictors of substance use incidence among immigrants. The current study describes substance use disorders in immigrants to Sweden, focusing on drinking culture in the country of origin and socioeconomic status (SES), and how these intersect with generational status to influence risk.

Methods: Using pseudonymized Swedish population registry data, we track onset of alcohol use disorder and drug use disorder in a longitudinal study of 815,778 first-generation immigrants and 674,757 second-generation immigrants from 64 countries over a 6-year period. Cox regression analysis estimated risks of alcohol and drug use disorders in second-generation immigrants compared to first-generation, and moderation analyses assessed interactions of generational status with country-of-origin per capita alcohol consumption and SES.

Results: Immigrants and second-generation immigrants originating from countries with high levels of alcohol consumption had higher risks for alcohol and drug use disorders. Immigrants with high SES had lower risks for alcohol and drug use disorders. The interaction between generational status and country-of-origin alcohol consumption was significant for drug use disorder (not for alcohol use disorder), with drug use disorder risk for second-generation immigrants being highest for those from countries with the lowest level of country-of-origin per capita alcohol consumption. The interaction between generational status and SES was significant for alcohol use disorder, with low-SES second-generation immigrants showing markedly higher risk than first-generation immigrants with comparable SES.

Conclusions: Among immigrants in Sweden, second-generation immigrants are at increased risk of developing alcohol and drug use disorders, particularly if they have lower SES. Policy and community attention to these high-risk subgroups in immigrant communities is warranted.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355220PMC
September 2021

Drinking cultures and socioeconomic risk factors for alcohol and drug use disorders among first- and second-generation immigrants: A longitudinal analysis of Swedish population data.

Drug Alcohol Depend 2021 09 18;226:108804. Epub 2021 Jun 18.

Alcohol Research Group, Public Health Institute, Emeryville, CA, USA; Community Health and Implementation Research Program, RTI International, Berkeley, CA, USA.

Background: Few longitudinal studies investigate predictors of substance use incidence among immigrants. The current study describes substance use disorders in immigrants to Sweden, focusing on drinking culture in the country of origin and socioeconomic status (SES), and how these intersect with generational status to influence risk.

Methods: Using pseudonymized Swedish population registry data, we track onset of alcohol use disorder and drug use disorder in a longitudinal study of 815,778 first-generation immigrants and 674,757 second-generation immigrants from 64 countries over a 6-year period. Cox regression analysis estimated risks of alcohol and drug use disorders in second-generation immigrants compared to first-generation, and moderation analyses assessed interactions of generational status with country-of-origin per capita alcohol consumption and SES.

Results: Immigrants and second-generation immigrants originating from countries with high levels of alcohol consumption had higher risks for alcohol and drug use disorders. Immigrants with high SES had lower risks for alcohol and drug use disorders. The interaction between generational status and country-of-origin alcohol consumption was significant for drug use disorder (not for alcohol use disorder), with drug use disorder risk for second-generation immigrants being highest for those from countries with the lowest level of country-of-origin per capita alcohol consumption. The interaction between generational status and SES was significant for alcohol use disorder, with low-SES second-generation immigrants showing markedly higher risk than first-generation immigrants with comparable SES.

Conclusions: Among immigrants in Sweden, second-generation immigrants are at increased risk of developing alcohol and drug use disorders, particularly if they have lower SES. Policy and community attention to these high-risk subgroups in immigrant communities is warranted.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355220PMC
September 2021

Mediational Pathways From Genetic Risk to Alcohol Use Disorder in Swedish Men and Women.

J Stud Alcohol Drugs 2021 05;82(3):431-438

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Objective: The purpose of this study was to clarify the mediational pathways from genetic risk for alcohol use disorder (AUD) to AUD itself.

Method: Using information on AUD status from first- through fourth-degree relatives obtained from national registries, we created a genetic risk score for AUD for the Swedish population. We first tested a simple mediational path model in males and females separately, with early onset externalizing psychopathology (EPP), internalizing psychopathology (IPP), and poor educational attainment (EA). We then tested a more complex model in a smaller, older sample of males that contained additional self-report measures from late adolescence.

Results: In our basic model, the largest mediational pathway from AUD genetic risk to AUD in both sexes was via high EPP followed by low EA and high IPP. The EPP pathway was considerably stronger in males, the low EA pathway was modestly stronger in females, and the IPP pathway was identical in both sexes. Our more complex model replicated the strong externalizing pathway to AUD, showing that it connected to key downstream risk factors such as early drug and alcohol use and low resilience.

Conclusions: Our models concurred in showing that the strongest mediational pathway for genetic risk to AUD includes externalizing symptoms and disorders, which in turn predict further key downstream risk factors. Pathways through lower EA and IPP had smaller effects. IPP had mixed effects (partly predisposing and partly protective) on downstream risk factors. The largest sex difference was a stronger externalizing pathway to genetic risk to AUD in males than in females.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328233PMC
May 2021

Top-down causation in psychiatric disorders: a clinical-philosophical inquiry.

Psychol Med 2021 Aug 2;51(11):1783-1788. Epub 2021 Jun 2.

Department of History and Philosophy of Science, University of Pittsburgh, Pittsburgh, PA, USA.

Psychiatry has long debated whether the causes of mental illness can be better explained by reductionist or pluralistic accounts. Although the former relies on commonsense scientific bottom-up causal models, the latter (which typically include environmental, psychological, and/or socio-cultural risk factors) requires top-down causal processes often viewed with skepticism, especially by neuroscientists. We begin with four clinical vignettes which illustrate self-interventions wherein high-order psychological processes (e.g. religious beliefs or deep interpersonal commitments) appear to causally impact the risk for or the course of psychiatric/behavioral disorders. We then propose a model for how to understand this sort of top-down self-causation. Our model relies centrally on the concept of a control variable which, like a radio tuning dial, can implement a series of typically unknown physical processes to obtain the desired ends. We set this control variable in the context of an interventionist account of causation that assumes that a cause (C) produces an effect (E) when intervening on C (by manipulating it) is associated with a change in E. We extend this framework by arguing that certain psychological changes can result from individuals intervening on their own mental states and/or selection of environments. This in turn requires a conception of the self that contains mental capacities that are at least partially independent of one another. Although human beings cannot directly intervene on the neurobiological systems which instantiate risk for psychiatric illness, they can, via control variables at the psychological level, and/or by self-selection into protective environments, substantially alter their own risk.
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http://dx.doi.org/10.1017/S0033291721001811DOI Listing
August 2021

Coronary heart disease in mothers and fathers of adult children with alcohol use disorders.

Addiction 2021 May 31. Epub 2021 May 31.

Department of Clinical Sciences Malmö, Center for Primary Health Care Research, Lund University and Region Skåne, Malmö, Sweden.

Background And Aim: Having a family member with an alcohol use disorder (AUD) may negatively affect a person's health. Our aim was to study the long-term risk of coronary heart disease (CHD) in parents who have an offspring with AUD.

Design: Cohort study with Cox regression models and co-sibling analyses.

Setting: Sweden.

Participants: From population registers, we selected all parent-offspring pairs in which the parent was born in Sweden between 1945 and 1965.

Measurements: Baseline was set when the offspring was 15 years old and AUD was assessed from medical and criminal registers. The parents were followed for CHD during a mean follow-up of 18 years. Hazard ratios (HRs) in mothers and fathers were calculated and adjusted for potential confounders (year of birth, age at childbirth, sex of the child, parent' AUD, educational level, and marital status).

Findings: In mothers, the adjusted HR for CHD was 1.24 (95% CI = 1.19-1.28) in relation to having a child with AUD. In fathers, the HR for CHD was lower than in mothers but still increased; the adjusted HR was 1.08 (95% CI = 1.05-1.12). In the co-sibling analyses, the HRs for mothers were similar to the HRs estimated from the population-based sample, but in fathers the association did not remain significant (HR = 0.98 [0.90-1.06]).

Conclusions: In Sweden, there appears to be an association between having an offspring with alcohol use disorder and increased risk of developing coronary heart disease. For fathers, the association did not remain in co-sibling analyses.
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http://dx.doi.org/10.1111/add.15591DOI Listing
May 2021

The patterns of family genetic risk scores for eleven major psychiatric and substance use disorders in a Swedish national sample.

Transl Psychiatry 2021 05 27;11(1):326. Epub 2021 May 27.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

To clarify the structure of genetic risks for 11 major psychiatric disorders, we calculated, from morbidity risks for disorders in 1st-5th degree relatives controlling for cohabitation effects, in the Swedish population born between 1932 and 1995 (n = 5,830,014), the family genetic risk scores (FGRS) for major depression (MD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), bulimia (BUL), anorexia nervosa (AN), alcohol use disorder (AUD), drug use disorder (DUD), ADHD, and autism-spectrum disorder (ASD). For all affected individuals, we calculated their mean standardized FGRS for each disorder. The patterns of FGRS were quite similar for MD and AD, and for AUD and DUD, but substantially less similar for BUL and AN, BD and SZ, and ADHD and ASD. While OCD had high levels of FGRS for MD and AD, the overall FGRS profile differed considerably from MD and AD. ADHD FGRS scores were substantially elevated in AUD and DUD. FGRS scores for BD, OCD, AN, ASD, ADHD, and especially SZ were relatively disorder-specific while genetic risk for MD and AD had more generalized effects. The levels of FGRS for BMI, coronary artery disease, and educational attainment across our disorders replicated prior associations found using molecular genetic methods. All diagnostic categories examined had elevated FGRS for many disorders producing, for each condition, an informative FGRS profile. Using a novel method which approximates, from pedigree data, aggregate genetic risk, we have replicated and extended prior insights into the structure of genetic risk factors for key psychiatric illnesses.
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http://dx.doi.org/10.1038/s41398-021-01454-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160183PMC
May 2021

Longitudinal Examination of the Impact of Resilience and Stressful Life Events on Alcohol Use Disorder Outcomes.

Subst Use Misuse 2021 25;56(9):1346-1351. Epub 2021 May 25.

Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.

Stressful life events (SLEs) are a risk factor for alcohol use problems, and there is a need for identification of factors that may offset this risk. Resilience is uniquely, inversely associated with alcohol use, but there remains a dearth of research examining the buffering effect of resilience toward alcohol use problems in the context of SLEs. This study used prospective data from an epidemiological twin sample (=7441) to test whether resilience at Time 1 would act as a buffer for new onset SLEs (e.g. assault, marital problems) against risk for alcohol dependence (AD) symptoms at Time 2. The final model, adjusted for familial relatedness and controlling for demographic covariates and Time 1 (lifetime) AD symptoms, identified significant main effects of resilience and SLEs; those with greater resilience at Time 1 reported fewer symptoms (β=-.087, <.001) and those with greater new-onset SLEs reported greater symptoms (β=.116, <.001) at Time 2. However, there was no significant interaction (β=-.008, >.05). Although findings further support the association of resilience and SLEs with AD, results do not support the conceptualization of resilience as a buffer against the impact of future life stressors on alcohol use outcomes. This suggests other factors may be more relevant for understanding protective factors for alcohol use problems or the relation between resilience and SLEs on alcohol use outcomes.
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http://dx.doi.org/10.1080/10826084.2021.1922454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418223PMC
August 2021

Psychiatric Resilience and Alcohol Resistance: A Twin Study of Genetic Correlation and Sex Differences.

Behav Genet 2021 Nov 24;51(6):619-630. Epub 2021 Apr 24.

Virginia Institute of Psychiatric and Behavioral Genetics, 800 E Leigh Street, Biotech One, PO Box 980126, Richmond, VA, 23298, USA.

Variability in psychiatric response following stressful/traumatic life events is frequently observed. There is also variability in propensity for alcohol use disorder (AUD) such that some can consume substantial amounts and not develop AUD symptoms whereas others develop an AUD. Our group has applied discrepancy-based approaches to capture psychiatric resilience (PR) and alcohol resistance (AR), both moderately heritable. This study sought to (1) examine the genetic and environmental correlation of these constructs and (2) model qualitative and quantitative sex effects. Data came from a large twin sample (N = 4501 twin pairs) with self-report measures and interviews assessing distress symptoms, stressful life events, alcohol use, and AUD. Correlated liability model results suggested a moderate degree of genetic correlation between PR and AR (0.54) due to the same genetic factors in males and females. Findings highlight the shared genetic predisposition of these resilience/resistance constructs while emphasizing the impact of unique environmental experiences.
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http://dx.doi.org/10.1007/s10519-021-10059-7DOI Listing
November 2021

Iterative Revision of the : An Interim Report From the Steering Committee.

Psychiatr Serv 2021 Apr 22:appips202100013. Epub 2021 Apr 22.

Department of Psychiatry, Columbia University Irving Medical Center, and New York State Psychiatric Institute, New York City (Appelbaum, Chair, DSM-5 Steering Committee); Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland (Leibenluft, Vice-Chair, DSM-5 Steering Committee, Section on Mood Dysregulation and Neuroscience); Virginia Institute for Psychiatric and Behavioral Genetics and Department of Psychiatry, Virginia Commonwealth University, Richmond (Kendler, Vice-Chair, DSM-5 Steering Committee).

After the publication of , the American Psychiatric Association moved to a model of iterative revision. Proposals for changes-including addition and deletion of diagnostic categories-can be made whenever data become available to support these changes. Criteria for consideration of proposals and a multistage review process have been created. This Open Forum reports on the first 3 years' experience since the opening of the submission portal in late 2017. Changes to date include adoption of a new diagnostic category, clarification of existing diagnostic criteria and text, and inclusion of new nondiagnosis codes for suicidal and nonsuicidal self-injury.
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http://dx.doi.org/10.1176/appi.ps.202100013DOI Listing
April 2021

Family Genetic Risk Scores and the Genetic Architecture of Major Affective and Psychotic Disorders in a Swedish National Sample.

JAMA Psychiatry 2021 Jul;78(7):735-743

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Importance: Family and genetic approaches have traditionally been used to evaluate our diagnostic concepts. Using a novel method, the family genetic risk score (FGRS), can we validate the genetic architecture of major affective and psychotic disorders in a national Swedish sample?

Objective: To determine whether FGRSs, calculated for the entire Swedish population, can elucidate the genetic relationship between major affective and psychotic disorders and clarify the association of genetic risk with important clinical features of disease.

Design, Setting, And Participants: This cohort study included the native Swedish population born from January 1, 1950, through December 31, 1995, and followed up through December 31, 2017. Data were collected from Swedish population-based primary care, specialist, and hospital registers, including age at first registration for a psychiatric diagnosis and number of registrations for major depression, bipolar disorder, and schizophrenia. Data were analyzed from October 15, 2020, to February 2, 2021.

Exposures: FGRSs for major depression, bipolar disorder, and schizophrenia calculated from morbidity risks for disorders in first- through fifth-degree relatives, controlling for cohabitation.

Main Outcomes And Measures: Diagnoses of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other nonaffective psychoses (ONAPs), age at registration, and number of registrations for major depression, bipolar disorder, and schizophrenia. Diagnostic conversion of major depression to bipolar disorder and ONAPs to schizophrenia was assessed by Cox proportional hazards regression models.

Results: The cohort included 4 129 002 individuals (51.4% male) with a mean (SD) age at follow-up of 45.5 (13.4) years. Mean FGRSs for major depression, bipolar disorder, and schizophrenia produced distinct patterns for major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and ONAPs with large separations between disorders. In major depression, bipolar disorder, and schizophrenia, high FGRSs were associated with early age at onset and high rates of recurrence: a high mean FGRS for bipolar disorder was associated with early age at onset (younger than 25 years, 0.11; 95% CI, 0.11-0.12) and higher recurrence (8 or more registrations, 0.11; 95% CI, 0.11-0.12) in major depression. The schizophrenia FGRS was separately associated with psychotic and nonpsychotic forms of major depression (0.10; 95% CI, 0.06-0.14 vs 0.03; 95% CI, 0.02-0.03) and bipolar disorder (0.22; 95% CI, 0.16-0.28 vs 0.11; 95% CI, 0.09-0.12). The bipolar disorder and schizophrenia FGRSs were associated with conversion from major depression to bipolar disorder (eg, hazard ratio, 1.70 [95% CI, 1.63-1.78] for high vs low bipolar FGRS) and ONAP to schizophrenia (eg, hazard ratio, 1.38 [95% CI, 1.27-1.51] for high vs low schizophrenia FGRS).

Conclusions And Relevance: In this Swedish cohort study, the FGRSs for major depression, bipolar disorder, and schizophrenia for the Swedish population clearly separated major affective and psychotic disorders from each other in a larger and more representative patient sample than previously possible. These findings provide possible validation, from a genetic perspective, for these major diagnostic categories. These results replicated and extended prior observations on more limited samples of the association of FGRS with age at onset, recurrence, psychotic subtypes, and diagnostic conversions.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060884PMC
July 2021

Prevalence of internalizing disorders, symptoms, and traits across age using advanced nonlinear models.

Psychol Med 2021 Apr 14:1-10. Epub 2021 Apr 14.

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.

Background: Most epidemiological studies show a decrease of internalizing disorders at older ages, but it is unclear how the prevalence exactly changes with age, and whether there are different patterns for internalizing symptoms and traits, and for men and women. This study investigates the impact of age and sex on the point prevalence across different mood and anxiety disorders, internalizing symptoms, and neuroticism.

Methods: We used cross-sectional data on 146 315 subjects, aged 18-80 years, from the Lifelines Cohort Study, a Dutch general population sample. Between 2012 and 2016, five current internalizing disorders - major depression, dysthymia, generalized anxiety disorder, social phobia, and panic disorder - were assessed according to DSM-IV criteria. Depressive symptoms, anxiety symptoms, neuroticism, and negative affect (NA) were also measured. Generalized additive models were used to identify nonlinear patterns across age, and to investigate sex differences.

Results: The point prevalence of internalizing disorders generally increased between the ages of 18 and 30 years, stabilized between 30 and 50, and decreased after age 50. The patterns of internalizing symptoms and traits were different. NA and neuroticism gradually decreased after age 18. Women reported more internalizing disorders than men, but the relative difference remained stable across age (relative risk ~1.7).

Conclusions: The point prevalence of internalizing disorders was typically highest between age 30 and 50, but there were differences between the disorders, which could indicate differences in etiology. The relative gap between the sexes remained similar across age, suggesting that changes in sex hormones around the menopause do not significantly influence women's risk of internalizing disorders.
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http://dx.doi.org/10.1017/S0033291721001148DOI Listing
April 2021

What is a mental disorder? An exemplar-focused approach.

Psychol Med 2021 04 12;51(6):894-901. Epub 2021 Apr 12.

Virginia Institute of Psychiatric and Behavioral Genetics and Departments of Psychiatry, and Human and Molecular Genetics, School of Medicine/Virginia Commonwealth University, VA, USA.

The question of 'what is a mental disorder?' is central to the philosophy of psychiatry, and has crucial practical implications for psychiatric nosology. Rather than approaching the problem in terms of abstractions, we review a series of exemplars - real-world examples of problematic cases that emerged during work on and immediately after DSM-5, with the aim of developing practical guidelines for addressing future proposals. We consider cases where (1) there is harm but no clear dysfunction, (2) there is dysfunction but no clear harm, and (3) there is possible dysfunction and/or harm, but this is controversial for various reasons. We found no specific criteria to determine whether future proposals for new entities should be accepted or rejected; any such proposal will need to be assessed on its particular merits, using practical judgment. Nevertheless, several suggestions for the field emerged. First, while harm is useful for defining mental disorder, some proposed entities may require careful consideration of individual v. societal harm, as well as of societal accommodation. Second, while dysfunction is useful for defining mental disorder, the field would benefit from more sharply defined indicators of dysfunction. Third, it would be useful to incorporate evidence of diagnostic validity and clinical utility into the definition of mental disorder, and to further clarify the type and extent of data needed to support such judgments.
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http://dx.doi.org/10.1017/S0033291721001185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161428PMC
April 2021

DECO: a framework for jointly analyzing de novo and rare case/control variants, and biological pathways.

Brief Bioinform 2021 09;22(5)

Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.

Motivation: Rare variant-based analyses are beginning to identify risk genes for neuropsychiatric disorders and other diseases. However, the identified genes only account for a fraction of predicted causal genes. Recent studies have shown that rare damaging variants are significantly enriched in specific gene-sets. Methods which are able to jointly model rare variants and gene-sets to identify enriched gene-sets and use these enriched gene-sets to prioritize additional risk genes could improve understanding of the genetic architecture of diseases.

Results: We propose DECO (Integrated analysis of de novo mutations, rare case/control variants and omics information via gene-sets), an integrated method for rare-variant and gene-set analysis. The method can (i) test the enrichment of gene-sets directly within the statistical model, and (ii) use enriched gene-sets to rank existing genes and prioritize additional risk genes for tested disorders. In simulations, DECO performs better than a homologous method that uses only variant data. To demonstrate the application of the proposed protocol, we have applied this approach to rare-variant datasets of schizophrenia. Compared with a method which only uses variant information, DECO is able to prioritize additional risk genes.

Availability: DECO can be used to analyze rare-variants and biological pathways or cell types for any disease. The package is available on Github https://github.com/hoangtn/DECO.
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http://dx.doi.org/10.1093/bib/bbab067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425460PMC
September 2021

Three Important Considerations for Studies Examining Pathophysiological Pathways in Psychiatric Illness: In-depth Phenotyping, Biological Assessment, and Causal Inferences.

JAMA Psychiatry 2021 Jul;78(7):697-698

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond.

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http://dx.doi.org/10.1001/jamapsychiatry.2021.0022DOI Listing
July 2021

Three Important Considerations for Studies Examining Pathophysiological Pathways in Psychiatric Illness: In-depth Phenotyping, Biological Assessment, and Causal Inferences.

JAMA Psychiatry 2021 Jul;78(7):697-698

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond.

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http://dx.doi.org/10.1001/jamapsychiatry.2021.0022DOI Listing
July 2021

Genome-wide analyses of smoking behaviors in schizophrenia: Findings from the Psychiatric Genomics Consortium.

J Psychiatr Res 2021 05 18;137:215-224. Epub 2021 Feb 18.

Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA. Electronic address:

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (r = 0.159; P = 5.05 × 10), cigarettes-smoked-per-day (r = 0.094; P = 0.006), and age-of-onset of smoking (r = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (r = 0.624, P = 0.002) and cigarettes-smoked-per-day (r = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096167PMC
May 2021

Kraepelin's final views on manic-depressive Illness.

J Affect Disord 2021 03 6;282:979-990. Epub 2021 Jan 6.

Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Box 980126, Richmond, VA, USA. Electronic address:

At the age of 65, 8 years after finishing his last textbook edition, Emil Kraepelin completed the final edition of his "Introduction to Clinical Psychiatry" which included a mini-textbook for students with a 7-page section on manic-depressive insanity (MDI), a disorder he had formally proposed 22 years earlier, and a series of new detailed case histories, 9 of which examined MDI. This text distills, near the end of his life, Kraepelin's perspective of the key features of MDI. The text and case histories are here translated into English for the first time. Kraepelin's views of the symptoms and signs of melancholia and mania closely aligned to those proposed by DSM-5. He emphasized the importance both of mixed features and the constitutional/personality foundations of MDI suggesting that a particular emotional disposition is often seen both inter-episodically in affected individuals (where they "fill the entire life") and in their unaffected relatives. He illustrates both these points in his case reports. His cases also made clear that for Kraepelin, classical Schneiderian psychotic symptoms and a full catatonic syndrome were consistent with a diagnosis of MDI.
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http://dx.doi.org/10.1016/j.jad.2020.12.200DOI Listing
March 2021

Increasing the resolution and precision of psychiatric genome-wide association studies by re-imputing summary statistics using a large, diverse reference panel.

Am J Med Genet B Neuropsychiatr Genet 2021 01 11;186(1):16-27. Epub 2021 Feb 11.

Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.

Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large-scale genome-wide association studies (GWAS). Methods for direct imputation of GWAS summary-statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage-disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500-subject coming from the 1000 Genome-Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic-mixture based solely on Z-scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary-statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post-traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS-studies.
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http://dx.doi.org/10.1002/ajmg.b.32834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247874PMC
January 2021

Julius Wagner von Jauregg, Otto Diem and research methods for assessing the contributions of hereditary burden to mental illness risk: 1902-1906.

Am J Med Genet B Neuropsychiatr Genet 2021 01 2;186(1):50-64. Epub 2021 Feb 2.

Free-lance German-English Translator, Cape Town, South Africa.

After decades of methodological stasis in 19th century psychiatric genetics, when uncontrolled studies reported high rates of hereditary burden in hospitalized patients, Koller completed the first controlled study in 1895. We pick up this narrative 7 years later when the well-known Julius Wagner v. Jauregg published a biting critique of the then current psychiatric genetics' literature. In 1905, partially in response to Wagner v. Jauregg, Otto Diem attempted to replicate and extend Koller's study. Wagner v. Jauregg then wrote a follow-up to his earlier critique in 1906, commenting on Diem's investigation. Themes discussed in this point-counterpoint included the necessity of statistical methods to draw meaningful conclusions about the impact of hereditary burden on mental illness, the required sample size and proper selection of controls, the classes of relatives which should optimally be studied, the problems of obtaining accurate information on familial illnesses, the nature of the disorders in families which contribute to mental illness risk and the common unquestioned dogmatic belief that insanity is very often due to hereditary causes. Both Wagner v. Jauregg and Diem spoke out forcefully against the common assumption that hereditary burden operated in a deterministic fashion and emphasized the need to consider other causes of illness.
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http://dx.doi.org/10.1002/ajmg.b.32832DOI Listing
January 2021

Julius Wagner von Jauregg, Otto Diem and research methods for assessing the contributions of hereditary burden to mental illness risk: 1902-1906.

Am J Med Genet B Neuropsychiatr Genet 2021 01 2;186(1):50-64. Epub 2021 Feb 2.

Free-lance German-English Translator, Cape Town, South Africa.

After decades of methodological stasis in 19th century psychiatric genetics, when uncontrolled studies reported high rates of hereditary burden in hospitalized patients, Koller completed the first controlled study in 1895. We pick up this narrative 7 years later when the well-known Julius Wagner v. Jauregg published a biting critique of the then current psychiatric genetics' literature. In 1905, partially in response to Wagner v. Jauregg, Otto Diem attempted to replicate and extend Koller's study. Wagner v. Jauregg then wrote a follow-up to his earlier critique in 1906, commenting on Diem's investigation. Themes discussed in this point-counterpoint included the necessity of statistical methods to draw meaningful conclusions about the impact of hereditary burden on mental illness, the required sample size and proper selection of controls, the classes of relatives which should optimally be studied, the problems of obtaining accurate information on familial illnesses, the nature of the disorders in families which contribute to mental illness risk and the common unquestioned dogmatic belief that insanity is very often due to hereditary causes. Both Wagner v. Jauregg and Diem spoke out forcefully against the common assumption that hereditary burden operated in a deterministic fashion and emphasized the need to consider other causes of illness.
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http://dx.doi.org/10.1002/ajmg.b.32832DOI Listing
January 2021

Philipp Jolly and his 1913 "the heredity of psychosis": Homogeneity versus heterogeneity of familial transmission and an early look at Mendelian models for manic-depressive illness and dementia praecox.

Am J Med Genet B Neuropsychiatr Genet 2021 03 22;186(2):90-100. Epub 2021 Jan 22.

Valentino Drive, Kirstenhof, Cape Town, South Africa.

Philipp Jolly's 1913 extensive monograph "The Heredity of Psychoses" provides, in both his detailed literature review and new pedigree study, an extensive assessment of a key issue in the psychiatric genetics of his day: the degree to which the familial transmission of psychiatric disorders was specific (or homogeneous) versus nonspecific (or heterogeneous). Contrary to a number of earlier observations, Jolly concludes that heterogeneous transmission is rare. Multiple psychiatric disorders can occur in one family because members of a family may have elevated predispositions to more than one disorder rather than one predisposition which increases risk for a wide range of conditions. A notable exception to this, he notes, is within manic-depressive illness (MDI), where different forms of illness run together within families. Jolly is also among the earliest investigators to evaluate simple Mendelian models for MDI and dementia praecox (DP). While his methods were primitive and contained only "eye-ball" examinations rather than statistical modeling, Jolly demonstrated considerable conceptual sophistication in the early application of such models. He concludes that DP is likely a recessive disorder. MDI, he states, is either a recessive condition or demonstrates "gender-based dominant heredity" where heterozygote females are affected, and heterozygote males are not.
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http://dx.doi.org/10.1002/ajmg.b.32831DOI Listing
March 2021

The state of the science in psychiatric genomics.

Psychol Med 2021 Oct 12;51(13):2145-2147. Epub 2021 Jan 12.

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.

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http://dx.doi.org/10.1017/S0033291720004900DOI Listing
October 2021
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