Subclinical Endophenotypes in Schizophrenia Aetiology and Nosology

This article is a short excerpt from this paper (in review): A call for the inclusion of religious schizophrenic disorder (RSD) in the DSM

It is well known to psychological science, genetic psychiatry, and behaviour genetics that certain people have genetically based vulnerabilities to certain kinds of mental disorders and personality disorders. One can use the following simple equation to express the contributions of nature (G or genetics) versus nurture (E or environment) to the formation of a particular trait or phenotype (P):

P = G + E (1)

The distinction between nature and nurture is often not helpful and can be blurred depending upon which disorder and which diagnostic criteria are of interest (Barlow, 2019; Crews et al., 2014; Schwartz, 1998). However, there are few cases – and the number of cases is diminishing as more data and superior experimental designs and techniques become available – where genetics is not a known, significant aetiological factor. Nonetheless, the picture for heritability of the DSM psychotic disorder schizophrenia is stubbornly complex and there are serious doubts surrounding the actual ratio for genetic versus environmental influences and the causal interactions between them. It’s likely that due to the complexity of the brain the range of possible disorders is enormous and nosology applied to type A personality disorders like schizophrenia will likely have to admit of a large cluster of sub-disorders in addition to, and across, existing conditions like schizophrenia, schizotypal disorder, schizoid disorder, and schizoaffective disorder. In other words - it is fair to expect that the conceptualisation and diagnostic criteria for schizophrenia will schism – with more than one set of conditions able to produce similar dysfunction and distress. (Perhaps there will be a biologically-based schizophrenia and also a variant with no basis – or markedly reduced basis - in polygenic-heritable structural defects.)

The ratio of nature to nurture in formation of personality and personality traits is considered to be well established - by numerous longitudinal and cross-sectional twin and family studies - to be approximately 40/60: 40% genetics and 60% environment (Fullerton, 2006; Kandler et al., 2021; Loehlin, 2012; Shifman et al., 2008). However, although there is little doubt about the existence of a heritable, genetic component of schizophrenia (in many cases) the degree to which the disorder schizophrenia is genetically based is controversial (Torrey & Yolken, 2019; Van Dongen & Boomsma, 2013). Estimates for the additive heritability of schizophrenia currently vary widely from 7-10% (Feldman, 2021) to 24%-55% based upon findings for known and suspected underlying subclinical endophenotypes (more specific, contributing, subclinical pathological abnormalities) (Greenwood et al., 2007) to 70-85% for non-additive inheritance in some monozygotic twin studies (Anttila et al., 2018; Legge et al., 2021; Purcell et al., 2009; Torrey & Yolken, 2019). Most endophenotype combinations are taken to map to various polygenic combinations but the exact mechanisms and triggers for onset are obscure in most cases.

To give an idea of the complexity of the epigenetic, diagnostic, methodological, and aetiological difficulties involved (and a major reason for focussing upon more specific subclinical endophenotypes): some researchers have found that effects of infectious agents in the environment such as (bacterial brain parasite) toxoplasma gondii are part of the (epigenetic and/or environmental) aetiology of schizophrenic symptoms in many cases (Torrey & Yolken, 2019). This is important because heritable or else epigenetic problems with truncated and overly dense neuronal dendrites and dendritic spines (thought to be associated with defective synaptic pruning) are different from an aetiology for schizophrenia that involves parasites in the brain (Toxoplasma gondii enter the brain and reside there) which cause or else exacerbate other problems with glutamatergic transmission, neuroplasticity, and oligodendrocyte function (but in the absence of malformed dendrites). A similar set of problems exists with interpreting the interaction between schizophrenia phenotypes/traits, genetics, and Epstein Barr virus (human herpesvirus 4), herpes simplex virus I and II, Rubella, and even influenza (Carter, 2009; Schretlen et al., 2010). (Human herpes simplex viruses take up residence in neural ganglia in the peripheral and central nervous system.)

Thus although (because, in fact) the biopsychosocial model is authoritative, there is a constantly increasing set of findings in psychogenetics and behaviour genetics supporting an ever-larger set of genetic markers and heritable genetic propensities for more and more personality types, behavioural propensities, personality disorders, and mental disorders. For example, not only are larger domain-level personality traits like extroversion, neuroticism, openness - and cognitive traits like intelligence - significantly genetically based or heritable (also on a recondite polygenic basis), but so are lower-level facets of trait factors in personality models such as conscientiousness, reliability, punctuality, organisation, moodiness, calmness, and lenience (Kaplan et al., 2015; Lee & Ashton, 2004; Samuel & Widiger, 2008).

Although there is much debate about its degree of heritability, the inclusion of schizophrenia itself as a disorder in the DSM is wholly uncontroversial due to the enormous available evidence from experiments and studies in behaviour genetics, psychogenetics, neuropsychology, health psychology, and cognitive psychology. Yet, subtypes, comorbidities, and variants – measured in terms of differing sets of symptoms with widely varying severity – may be less stable and less persistent in patients. Moreover, since there is much uncertainty about the aetiology and degree of heritability in many cases where there are confounding biological and epigenetic variables, it is more likely that the set of subtypes and comorbidities of the disorder will increase in the DSM even if the primary phenotype is consolidated.

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