Addressing a Conundrum: Why, According to the Genome-Wide Association Study and Psychiatric Genome Consortium are Clusters of Gene Loci Variants Associated with Schizophrenia Found Scattered in Non-Schizophrenia Populations? A Consilience

Addressing a Conundrum: Why, According to the Genome-Wide Association Study and Psychiatric Genome Consortium are Clusters of Gene Loci Variants Associated with Schizophrenia Found Scattered in Non-Schizophrenia Populations? A Consilience

Nicholas Pediaditakis, M.D., D.L.F.A.P.A.
ECU Brody School of Medicine, Dept of Psychiatric Medicine
Correspondence:5100 Lead Mine Rd, Raleigh, NC 27612, USA
Phone: (919) 418-2278 Fax: (919) 787-0710

ABSTRACT

Objective: Current findings regarding genetic origins and mechanisms of major mental disorders need to be reinterpreted.

Scope: The cluster of gene loci variants associated with schizophrenia may be redefined as the expression of lopsided, phenotypic traits comprising the premorbid personality of vulnerable people. These genetic traits originate mainly from evolutionary pressures making up the asocial components of human nature characterized by self absorption, aloofness, and lack of connectedness. The eusocial traits that originate from pressures on the social aspects of human experience such as empathy, altruism, bonding, and mutuality are underrepresented or otherwise absent for the disorder. These two clusters of behavioral traits constitutes our normal human nature.
Results: Lopsided genetic traits create a pool of at-risk individuals who probabilistically develop schizophrenia, but, at a much higher rate than the 1-2% prevalence in the general population. The periodic epiphenomena of characteristic symptoms define the onset and subsequent periodic relapse for the disease. They consist of antithetical substitutes such as apathy alternating with agitation, ambivalence versus either-or thinking, defective associations and the co-occurrence of generic, psychotic symptoms. These symptoms result from disturbances in the overall coordination of brain function catalyzed by underlying genetic traits. Same clusters of gene loci associated with schizophrenia are also found congregated in individuals manifesting other mental disorders at a much higher rate compared to the general population, but, they may not necessarily invariably develop the disease. This will help identify the circumstances that compromise the overall synchrony and coordination of brain function for members of these populations whom may otherwise be susceptible to mental disorders.

Promising answers to the posed conundrum relate to the known but overlooked collective significance of recent genetic research findings (1-5).These must be reconciled with empirical clinical evidence (6-10), together with recent findings from evolutionary biology (11-13) regarding the underlying structural origin and mechanism in the development of major mental disorders (MMDs) such as schizophrenia, bipolar affective disorder (BPAD), obsessive compulsive disorder (OCD), and related others.

Genetic findings indicate a common neural developmental origin (5). This is bolstered by clinical observations— they all share similar characteristics in their expressions, for example, they remit and relapse with time, albeit, less frequently in the case of schizophrenia and often overlap and alternate in their relapses (14,15). Generally, they are messy in their clinical presentation and rarely conform to the procrustean, categorical guidelines of the DSM series, now V (7). In fact, the ever changing terms used in the series through the years act as a semantic trap, hindering rather than elucidating a patient’s condition. In addition, comorbidities are ubiquitous (16-18), and are currently often treated by the same types of medications.

In actual practice, we treat symptoms, not syndromes, by commonly employing anti-anxiety, anti-psychotic, anti-convulsant/lithium, and antidepressant medications alone or in combination tailored for each patient. Significantly, schizophrenia and BPAD readily remit, at least for a time. Significantly, in early history, patients also respond to electroconvulsive therapy (ECT) (19-22). Sometimes, MMDs even remit spontaneously with time, although not as often for schizophrenia. These disorders, when expressed clinically should be viewed as periodic epiphenomena of the underlying, preexisting, lopsided personality traits (6,9,10,23), at least in their early stages.

These epiphenomena, in addition to their accompanying generic psychoses — to be addressed later — express symptoms made up of antithetical substitutes. In the case of schizophrenia, these symptoms consist of ambivalence, i.e., the coexistence of opposing feelings or attitudes, apathy alternating with agitation, an inability to accommodate ambiguity, concretistic, either-or thinking and disordered associations, non-sequitur thinking and difficulties in social interaction as in the case of autism (24). These symptoms are superimposed invariably on preexisting lopsided, clusters of genetic traits— the inborn behavioral propensities— and mixed to some degree, varies for each afflicted individual. Preexisting personality traits include, among possibly others, self-absorption, limited empathy, aloofness, a felt inner void, a preference for being alone or an aversion to connect with others. The sufferers have difficulties with normal emotional responses in given situations and an aversion to social interaction.

These personality traits constitute the elements of the premorbid personality. Other studies discussing the premorbid personality use somewhat different terms that, are similar in meaning. E. Kraepelin, E. Bleuer, and K. Schneider, among others (25), each offered nosological schemata and categorizations of symptoms. These schemata contain the same core characteristic symptoms enumerated above albeit, differently named and categorized. In their efforts to encompass the superimposed disease on the underlying morbid cluster of personality traits, as well as the variable expression of the disorders, they obscured rather than elucidated the mechanisms.

There also exist variability of the underlying personality traits in the expression for other MMDs such as narcissitic and borderline personality disorders. Such variability reflects the almost infinite, small, variable expressions of each individual, even though they are all within the boundaries of human nature as well as specific ―lopsided-or-not, personality types — like a kind of ―theme with variations. It follows that the probabilistic occurrence of schizophrenic episodes result in different forms of the disease, as is the case in clinical reality. Different combinations of the genes loci associated with schizophrenia create different forms in the expression of the disease. Emil Kraepelin, himself stated with perspicacity that different forms of schizophrenia do not represent the expression of one particular, pathological process, but, rather, indicate the personality trait in which these processes unfold (25). Sigmund Freud called the mental disorders — using the terms of his time — ―Narcissistic Neurosis, correctly perceiving the underlying, lopsided, selfish component of a patient’s difficulties to connect and empathize as a “lack of object relations.(26) He attributed a mental disorder to the development of epigenetic events (26), though, incorrectly, in the face of current clinical and genetic evidence.
To reiterate, the cluster of gene loci-variants associated with schizophrenia do not directly cause the disorder (1). However, the implicated genes may express themselves as lopsided, phenotypic, genetic traits comprising the premorbid personality, thus conferring vulnerability for the disorder. While these premorbid, genetic traits are a prerequisite of a mental disorder, their presence do not invariably lead to it. The pool of people carrying these cluster of genetic loci, in addition to the expression of the premorbid personality show a higher probability to display a range of personality traits ranging from being asocial to out-right antisocial and often also exhibit scientific or artistic ability to be discussed below.

These lopsided cluster of traits differs greatly from normally occurring types that comprise readily observable temperamental variability in humans. The premorbid elements can often be masked by learned civility and even simulated gregariousness. Even patients with bipolar disorder as well as OCD mask feelings of an inner void and unconnectedness. In BPAD, the latter underlies the patient’s undue emotionality. The sufferers readily confirm a chronically felt emptiness or boredom and a sense of inner void, common to many mental disorders (6).

Such temperamental clusters originate mainly from evolutionary pressures on the individual, but E.O. Wilson and his co-workers discovered that such clusters of traits comprise only one part of human nature. They propose that the other part originates from evolutionary pressures on the social aspects of human experience such as empathy, connectedness, altruism, mutuality/cooperativeness among others (11-13). All of these traits are deficient or lacking in schizophrenics, as well as in other MMDs. Normally, as he explains, we balance traits that are unamalgamated and chimera-like. They make us successful, but, conflicting, social animals. He further stated that we exist in unstable compromises between ourselves and those close to us within our own tribe and adjoining ones.
Significantly, the clinical expression of schizophrenia comprised of the aforementioned characteristic symptoms should be considered the expression of a temporary disturbance of the normal, overall operating mode of brain function which often becomes permanent in schizophrenia. This periodic neurological dysfunction is strikingly similar to the periodic occurrence of atrial fibrillation, a disorder of the sino-atrial (SA) node that, on onset, easily converts to normal rhythm with electroconvulsive therapy but, often becomes permanent later on and impervious to it. In the case of schizophrenia, faculties of orderly sequitur thinking, coordination of thinking with affect, and appropriateness to outside circumstances are expressed in an either-or, uncoordinated fashion — a kind of “Psychic Parkinsonism (6,27). This phenomenon has been previously mentioned by Nancy Andreasen, using the term ―Cognitive Dysmetria (28). The overall, normal mode of brain function whose significance has been overlooked in the studies and modeling of mental disorders ensures the synchrony, coordination, elegance, subtlety, smoothness, and more-or-less-ness in the expression of all higher mental faculties (29,30).

Higher mental faculties, especially in schizophrenia involve the ability to think with feelings and behave appropriately to a given situation. In bipolar disorder, it usually involves the faculty of mood modulation. This faculty, when uncoordinated is expressed as depressive versus manic disorder-an ―either-or phenomenon. It is important to note, that in the case of intermittent, major, depressive disorder, the manic phase is minimally experienced by the patient as a transient emotional rush, readily recounted when asked. Similarly, the algorithmic faculty of scheduling, sequencing future actions, and fore-planning — a normal but, often ignored faculty (30)— is often expressed as uncoordinated, obsessive compulsive-like behavior including antithetical symptoms of ambivalence, ―either-or behavior, procrastination, equivocation, continuous doubting, an inability to accommodate ambiguity, entrainment of ideas and actions alternating with repetitiveness in a ritualistic manner (30). The sufferer also readily admits feeling emotionally numb when asked!

These phenomena can also be readily witnessed in a spectacular form in borderline disorder during frequent, extreme psychotic occurrences of antithetical symptoms often lasting only minutes. They are made up of antithetical stark substitutes spanning across all of the sufferer’s higher mental faculties (31,32). They are mentioned tautologically in the literature as ―emotional instability (33). The main underlying, extreme, temperamental traits for this disorder include hyperintensity combined with a lack of empathy and an undue, self-absorption (33).

Overall coordination and synchrony of the normal mode for all higher mental faculties are the very essence and elegance of normally functioning humans, especially in social interaction and behavior. This overall property can only be considered an emergent phenomenon of complexity. There are many less complex examples ubiquitous in our natural living system, such as the elegant choreography in the sky exhibited by a flock of of starlings (i.e., murmuration). Each bird obeys its own algorithm expressed in the presence of its companions in flight— a phenomenon not yet elucidated in its details.

The overall coordinating function of the brain during onset and relapse of schizophrenia should be considered a pathologically ordered state with its either-or symptomatology (6). However, schizophrenics appear, even to laymen strange in their countenance, demeanor, and social behavior (35). To use an analogy, the exhibited symptoms are akin to the cacophony that ensues in an orchestra when the conductor suddenly departs. Often, these symptoms revert to a normal state, at least temporarily, with ECT, especially during the early onset of the disease. Although, temporary recovery with ECT is significant in its implications, it is not considered such to the current, clinical modeling of mental disorders.

Following remission, residual symptoms appear as an underlying, extreme, temperamental lopsidedness. This trait should be considered together with the concomitant dearth of eusocial traits as the very cause of periodic instability. During a relapse, the simultaneous appearance of psychosis with its characteristic hallucinations and delusions are an attempt by the brain to make sense of an underlying dysfunction. They are “generic” phenomena, indeed, that resemble other disruptions in brain function such as in high fever, brain trauma, toxicity, or the aftermath of heart surgery, among many others treated by the same anti-psychotic medications.

Importantly, creative individuals tend to share these aforementioned, aberrant temperamental traits to various degrees as factors that enhance their talent. When gifted with genius, brilliance, tenacity, accomplishments, and curiosity, their creativity also makes them vulnerable to and conducive to the development of a mental disorder (35,36). Nicola Tesla and Issac Newton are two well-known examples of creative individuals having concomitant mental disorders. The list of extremely creative individuals exhibiting lopsided temperamental traits is very long indeed.

The probabilistic occurrence of the first episode of schizophrenia usually occurs around late adolescence – possibly triggered by hormones, pruning, and social pressures. Currently, it is amenable to prediction only by statistical methods. The prevalence rate for the general population worldwide, irrespective of culture, is approximately 3% to 6% for all three major mental disorders combined, and 1-1.5% for schizophrenia (37, 38). This can be considered a downside of certain evolutionary advantages in being human.

The above assessments point toward new and promising directions for studies in behavioral genetics. This paper is based on the collective clinical findings of these phenomena found amongst 12,000 individual patients I treated and followed in some cases for over five decades from one generation to the next. This is in conciliation with genetic findings, clinical studies, and recent findings in evolutionary biology. The proposition that schizophrenia is expressed as a periodic epiphenomenon offers an answer to the question arising out of the so called third law of behavioral genetics proposed by Eric Turkheimer and Irving Gottesman stating, ―A substantial portion of the variation in complex human behavioral traits is not accounted for by the effects of genes or families(39). The etiological influence of genetics cannot explain why only 50% of cohorts of monozygotic twins suffering from schizophrenia develop the disorder instead of the expected 100% (40).

To summarize; ―While much of the known genomic variation for schizophrenia is observed across many global populations, population-specific variations are substantial and associations could be masked in a mixed sample (1). Studies of personality types in their described form are very important because, based on genetic and clinical evidence, the same clusters of gene loci associated with schizophrenia can be found congregated in individuals vulnerable to major mental disorders at a much higher rate compared to the general population, but, invariably not expressing the disorder. The traditionally recognized cluster of five personality traits includes neuroticism, antagonism versus agreeableness, extroversion versus introversion, and conscientiousness versus openness to new experience. They could be renamed by using adjectives similar in meaning but, better reflecting their dual evolutionary origins. Then, by modifying existing genetic tests, geneticists and clinicians alike can identify vulnerable groups. This will enable researchers to discern patterns and relationships between genes, clusters of genes and behavioral traits involved in the expression of temperamental phenotypes in individuals susceptible to a mental disorders. Importantly, this will also enable identification of circumstances and triggers that compromise the overall synchrony and coordinating faculty of brain function for these populations that results for some, in the periodic, epiphenomena of schizophrenia and other mental diseases.

BIOGRAPHICAL SKETCH
Nicholas Pediaditakis earned his Bachelor of Science and Doctor of Medicine degrees in 1954 from the Aristotelian University of Salonika, Greece. He was honorably discharged as a Sargent from the Greek Army Medical Corps in 1952. In 1955, he joined the doctoral program in Psychiatry at Fair View Park Hospital in Cleveland, Ohio. In 1959, he completed his Psychiatric Residency at the University of Colorado Medical Center in Denver.
Dr. Pediaditakis was the Medical Director of the Wake County Comprehensive Mental Health Center in Raleigh, North Carolina from 1962-1983. Since then, he has been working as a part-time consultant at out-patient clinics and an individual practitioner in North Carolina and has published numerous articles on psychiatry. He is a distinguished, life fellow of the American Psychiatric Association.

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30 Nicholas Pediaditakis, M.D., D.L.F.A.P.A.

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