Irish study of high-density schizophrenia families: Field methods and power to detect linkage

Kendler, Kenneth S.; O’Neill, Francis; Burke, John; Murphy, Bernadette; Duke, Fiona; Straub, Richard E.; Shinkwin, Rosmarie; Nuallain, Maurin Ni; Maclean, Charles; Walsh, Dermot

doi:10.1002/(sici)1096-8628(19960409)67:2<179::aid-ajmg8>3.0.co;2-n

Cited by 94 publications

(23 citation statements)

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“…In a study of a large set of carefully diagnosed Irish sibling pairs concordant for schizophrenia, the siblings substantially resembled one another in the level of manic and depressive symptoms demonstrated during their course of illness (29). This study group did not have any appreciable admixture of mania or schizoaffective disorder because no increased risk for bipolar illness in relatives was observed (30). This pattern of results is consistent with the hypothesis that there are familial factors that influence the probability of demonstrating mania-like symptoms in individuals with schizophrenia but that these factors do not increase the risk for mania in individuals without schizophrenia.…”

Section: Hierarchy and Heritability: The Role Of Diagnosis And Modeling In Psychiatric Geneticssupporting

confidence: 85%

Hierarchy and Heritability: The Role of Diagnosis and Modeling in Psychiatric Genetics

Kendler¹

2002

AJP

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Section: Hierarchy and Heritability: The Role Of Diagnosis And Modeling In Psychiatric Geneticssupporting

confidence: 85%

Hierarchy and Heritability: The Role of Diagnosis and Modeling in Psychiatric Genetics

Kendler¹

2002

AJP

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“…I have to admit an auto‐biographical influence here. It was only shortly after my brash days as a biological psychiatrist seeking to find “ the ” neurochemical cause for schizophrenia that I set out to find “ the ” gene for schizophrenia by studying large high‐density pedigrees in Ireland. Both efforts were driven by a naïve view of schizophrenia that it had a single essence – one biological secret which if understood would explain all we wanted or needed to know about the disorder.…”

Section: Discussionmentioning

confidence: 99%

The nature of psychiatric disorders

Kendler

2016

World Psychiatry

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A foundational question for the discipline of psychiatry is the nature of psychiatric disorders. What kinds of things are they? In this paper, I review and critique three major relevant theories: realism, pragmatism and constructivism. Realism assumes that the content of science is real and independent of human activities. I distinguish two "flavors" of realism: chemistry-based, for which the paradigmatic example is elements of the periodic table, and biology-based, for which the paradigm is species. The latter is a much better fit for psychiatry. Pragmatism articulates a sensible approach to psychiatric disorders just seeking categories that perform well in the world. But it makes no claim about the reality of those disorders. This is problematic, because we have a duty to advocate for our profession and our patients against other physicians who never doubt the reality of the disorders they treat. Constructivism has been associated with anti-psychiatry activists, but we should admit that social forces play a role in the creation of our diagnoses, as they do in many sciences. However, truly socially constructed psychiatric disorders are rare. I then describe powerful arguments against a realist theory of psychiatric disorders. Because so many prior psychiatric diagnoses have been proposed and then abandoned, can we really claim that our current nosologies have it right? Much of our current nosology arose from a series of historical figures and events which could have gone differently. If we re-run the tape of history over and over again, the DSM and ICD would not likely have the same categories on every iteration. Therefore, we should argue more confidently for the reality of broader constructs of psychiatric illness rather than our current diagnostic categories, which remain tentative. Finally, instead of thinking that our disorders are true because they correspond to clear entities in the world, we should consider a coherence theory of truth by which disorders become more true when they fit better into what else we know about the world. In our ongoing project to study and justify the nature of psychiatric disorders, we ought to be broadly pragmatic but not lose sight of an underlying commitment, despite the associated difficulties, to the reality of psychiatric illness. A foundational question for the discipline of psychiatry is the nature of what we treat and study: psychiatric disorders. What kinds of things are they? This question can be fruitfully addressed from several perspectives. We could, for example, ask about their etiology and contribute to the long running argument about whether they are better understood from a psychological versus a biological perspective. We could explore their historical development and the differentiation of psychiatric from neurologic conditions. But I will not be taking such approaches here. Rather, my questions are more philosophical (or, to be more precise, metaphysical) in nature.I will review and critique three major theories about the nature of psychiatric disorders: r...

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“…Second, Diagnostic ascertainment of ISHDSF required two first-degree relatives with a diagnosis of SCZ or PO-SAD. Therefore, the various diagnostic categories in the ISHDSF diagnostic schema are not equally represented across all families 28 . For example, the lower number of individuals satisfying broad and very broad diagnostic schema in the families, means that the power of analysis in those subgroups is lower.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families

Ahangari

Gentry

et al. 2021

Preprint

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ImportanceMultiplex schizophrenia families have higher recurrence risk of schizophrenia compared to the families of singleton cases in the population, but the source of increased familial recurrence risk is unknown. Determining the source of this observation is essential, as it will define the relative focus on common versus rare genetic variation in case-control and family studies of schizophrenia.ObjectiveTo evaluate the role of common risk variation in the recurrence risk of schizophrenia, by comparing the polygenic risk scores in familial versus ancestry matched singleton cases of schizophrenia.DesignWe used the latest genome-wide association study data of schizophrenia (N=166,464) to construct polygenic risk scores in multiplex family members, singleton cases and controls. To account for the high degree of relatedness in the samples, analyses were carried out using a mixed effects logistic regression model with the family structure modeled as a random effect.SettingPopulation and family based.ParticipantsWe used a large, homogenous sample of 1,005 individuals from 257 families from the Irish Study of High-Density Schizophrenia Families, 2,224 singleton cases and 2,284 population controls all from the population of the island of Ireland.ExposuresPolygenic risk scores, diagnostic categories, familial or singleton case status.Main outcomes and measuresThe primary outcomes were the mixed effects logistic regression results generated from comparison between different groups.ResultsPolygenic risk scores in singleton cases did not differ significantly from familial cases (p=0.49), rejecting the hypothesis that an increased burden of common risk variation can account for the higher recurrence risk of schizophrenia in multiplex families.Conclusions and relevanceThis study suggests that a higher burden of common schizophrenia risk variation cannot account for the increased familial recurrence risk of schizophrenia in multiplex families. In the absence of elevated polygenic risk scores in multiplex schizophrenia families, segregation of rare variation in the genome and environmental exposures unique to the families may explain the increased multiplex familial recurrence risk of schizophrenia. These findings also further validate the concept of a genetically influenced psychosis spectrum in multiplex schizophrenia families as shown by a continuous increase of common risk variation burden from unaffected relatives to familial cases of schizophrenia in the families.

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Irish study of high-density schizophrenia families: Field methods and power to detect linkage

Cited by 94 publications

References 51 publications

Hierarchy and Heritability: The Role of Diagnosis and Modeling in Psychiatric Genetics

Hierarchy and Heritability: The Role of Diagnosis and Modeling in Psychiatric Genetics

The nature of psychiatric disorders

Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families

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