GENETICS OF PARANOIDPERSONALITYDISORDER
Authors: Pomohaibo V. , Berezan O. , Petrushov A. 
Published: November 2023

Paranoid personality disorder (PPD) is characterized by the following leading features: excessive sensitivity to failures and refusals; inclination to persistently endure even minor insults and injuries or slights, refusing to forgive them; suspicion and distortion of facts, interpretation of friendly or neutral actions of other people as hostile or contemptuous; unjustified suspicions of sexual infidelity of a partner; unfounded concern about the imaginary conspiracy of events both in relation to himself and around the world; feeling of one's own usually exaggerated significance; unfounded militant defense of their personal rights. The prevalence of PPD is 2.3-4.4% and is more often diagnosed in men. Heritability of PPD varies from 28% to 66%.

By now various authors have described 16 genes associated with the development of PPD: SLC6A4, COMT, CACNA1C, NOS1AP, DYNC1I1 and 11 genes of mitochondrial complex 1. The SLC6A4 gene (17q11.2) encodes a reverse serotonin transporter. A slight deletion in the promoter of this gene reduces its activity and can minimize the expression of paranoid traits. The product of the COMT gene (22q11.21) is actively involved in dopamine metabolism. A G-to-A transition atcodon 158 of this gene increases its activity by 3-4 times and, as a consequence, decreases dopamine expression in the prefrontal cortex, which causes paranoid symptoms of personality disorders. The CACNA1C gene (12p13.33) encodes a protein that plays an important role in the formation and activity of brain neurons. The single nucleotide polymorphism rs1006737, located in the 3rd intron of this gene, is associated with PPD, schizophrenia, schizotypal personality disorder, major depressive disorder and bipolar disorder.

Mitochondrial complex 1 and cellular bioenergetic pathways play a significant role in the etiology and features of PPD and schizophrenia. Significant changes in expression of 11 genes were detected in patients with PPD compared to the control sample. Expression of genes NDUFS1 (2q33.3), NDUFV1 (11q13.2), NDUFV2 (18p11.22), NDUFB5 (3q26.33), NDUFB9 (8q24.13), NDUFA13(19p13.11), NDUFA8 (9q33. 2) and NDUFA5 (7q31.32) was increased, and the genes NDUFB11 (Xp11.3), NDUFS7 (19p13.3) and NDUFS8 (11q13.2) were decreased. The NDUFS1 gene expression was particularly high. None of the sevenmitochondrial genes showed a change in expression,which may reduce the importance of a maternal patternin the heritance of PPD.The results of the study showed that the NDUFS1 gene may be a specific marker for PPD.

In the presence of relevant genetic factors certain environmental conditions can provoke the development of PPD. It is possible to predict PPD on the presence of NOS1AP (1q23.3) gene polymorphisms and childhood abuse. The protein encoded by this gene is involved in the functioning of brain synapses. There is shown that emotional violence and SNPs rs348624 and rs4145621, located respectively in the 9th exon and 3rd intron of the NOS1AP gene, reliably predict PPD.

In addition to described above 16 genes, whose variants are reliably involved in PPD, various researchers have identified at least 8 other genes that are likely to be associated with PPD, although they have been identified in the study of other mental disorders, mainly schizophrenia.

A review of available scientific sources on PPD genetics shows that research of this problem isin its beginning. It is necessary to expand and deepen these studies on the basis of the most modern molecular genetic technologies, one of which is the genome-wide associations study. This technology makes it possible not only to detect candidate genes, but also to determine the nature of mutations that cause hereditary disease. Such mutations can be single nucleotide polymorphisms, small insertions / deletions and changes in the number of copies. In addition, they can be located not only within genes (in exons and introns), but also in intergenic regions of DNA. Gene expression can be affected not only by mutations within its exons, but also by mutations within its introns and intergenic DNA regions.