The Genetics of Schizophrenia—Is This a Time for Revising the ‘Method’?

The Genetics of Schizophrenia—Is This a Time for Revising the ‘Method’?

Rais Theodor

US Psychiatry 2009;2(1):41-4

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Abstract
This article reviews the progress in research into the genetics of schizophrenia together with new discoveries in the field of small RNAs, human genome ‘pyknons,’ the use of convergent functional genomics, and phenochipping for psychotic disorders. It addresses their effect on the understanding of the etiological models of schizophrenia, and brings to light the failure of long-standing endeavors to generally build valid models. This direction did not achieve the expected breakthrough in modeling complex illnesses such as schizophrenia. The article raises the question of elaborating different tools that would switch attention from general models of diseases to modeling specific and complex treatment plans for individual patients.

Keywords
Genetics, schizophrenia, modeling, small RNA

Disclosure: The author has no conflicts of interest to declare.
Received: March 25, 2008 Accepted: July 14, 2008
Correspondence: Theodor Rais, MD, Department of Psychiatry, University of Toledo, 2801 W Bancroft, Toledo, OH 43606-3390. E: theodor.rais@utoledo.edu

The transmission of psychiatric illnesses in general, and of schizophrenia in particular, is a complex phenomenon that occurs at the intersection of different genetic and environmental interactions.1–4 The phenotypes of these illnesses are sometimes unclear, and comorbidity with another illness may further complicate the clinical picture.5,6 Linkage studies were used extensively in psychiatric research because of their ability to localize foci for Mendelian transmitted diseases. These studies utilized different designs, such as the traditional and sib-pair designs, and were performed in large populations.7,8 Unfortunately, most of these studies were not replicated.9 Some authors such as Gershon expressed the idea that the statistical power needed to find a significant locus is approximately 5–10%, and in this situation most samples will not replicate the linkage even if it is an accurate one.10 It is clear that this explanation does not solve the problem of linkage studies in understanding complex diseases and also does not take into account the context of the encounter between the environmental and the multiple genetic factors in the apparition of many complex diseases.11–13

The candidate gene approach was preferred by many scientists due to the desire to verify certain genetic hypotheses that were raised by insights and experimental facts about different diseases.14,15 The studies were relatively simple to design and, using specific epidemiological tools, enhanced their accuracy.5,16 However, even in large samples the stratification of the population had the potential to lead to false-positives. The researched allele variant had to be desirable in terms of being functional and biologically relevant. The newer approaches have the ability to test the effects of two markers and their statistical interactions.

The use of endophenotypes or trait markers was meant to identify a trait that is more common in the ill population than in the general population. This trait will also be displayed by unaffected family members (who are carriers of the predisposing allele). The trait that is chosen needs to be heritable, common in close relatives, and stable over time, and must not change under the influence of medications or other treatments for the main illness.17 A classic example is a low response to alcohol in the offspring of alcoholics18–20 or the deficit in smooth pursuit of eye tracking movements in the case of relatives of schizophrenia patients.20,21 Recent novel techniques include single nucleotide polymorphisms (SNPs) scored on DNA chips that allow the simultaneous testing of thousands of candidate genes and work with large samples of patients.22–24 There are also whole genome scans in siblings with certain diseases, for example the work undertaken by Risch, who performed a genome scan in siblings with autism and identified shared alleles in every chromosomal region.

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