Post‐zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia

Abstract

Background Monozygotic twins are valuable in assessing the genetic vs environmental contribution to diseases. In the era of complete genome sequences, they allow identification of mutational mechanisms and specific genes and pathways that offer predisposition to the development of complex diseases including schizophrenia. Methods We sequenced the complete genomes of two pairs of monozygotic twins discordant for schizophrenia (MZD), including one representing a family tetrad. The family specific complete sequences have allowed identification of post zygotic mutations between MZD genomes. It allows identification of affected genes including relevant network and pathways that may account for the diseased state in pair specific patient. Results We found multiple twin specific sequence differences between co-twins that included small nucleotides [single nucleotide variants (SNV), small indels and block substitutions], copy number variations (CNVs) and structural variations. The genes affected by these changes belonged to a number of canonical pathways, the most prominent ones are implicated in schizophrenia and related disorders. Although these changes were found in both twins, they were more frequent in the affected twin in both pairs. Two specific pathway defects, glutamate receptor signaling and dopamine feedback in cAMP signaling pathways, were uniquely affected in the two patients representing two unrelated families. Conclusions We have identified genome-wide post zygotic mutations in two MZD pairs affected with schizophrenia. It has allowed us to use the threshold model and propose the most likely cause of this disease in the two patients studied. The results support the proposition that each schizophrenia patient may be unique and heterogeneous somatic de novo events may contribute to schizophrenia threshold and discordance of the disease in monozygotic twins. Electronic supplementary material The online version of this article (10.1186/s40169-017-0174-1) contains supplementary material, which is available to authorized users.

Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia

“…Under these circumstances, there is an imperfect alternative that may help assess the feasibility of the expandedthreshold-liability model in schizophrenia. Here, monozygotic twin pairs discordant for schizophrenia (MZD) may be used to represent an appropriate resource for testing the expandedthreshold-liability model for schizophrenia (88,89). Recall that members of the MZD pair begin life as a single zygote but develop independently as two different individuals (somas).…”

“…may serve as a proxy for occurrence of "early" somatic mutations that may also be present in neuronal cells. Indeed, DNA from the blood of MZD twins has been shown to be not 100% identical (74,89,92). They carry a variety of sequence differences, epigenetic and genetic, that must result from postzygotic events.…”

“…Interestingly, the complete DNA sequence and genome-wide DNA methylation (88,89) data on the blood DNA from two MZ twin pairs discordant for schizophrenia and their parents available in the literature allows us to assess any involvement of PMZs in this disease. The analysis of these data has allowed an assessment of a large number of disease associated mutations (http://www.szdb.org) reported in the blood DNA.…”

Association of the Polymorphism of GSTP1 with the Susceptibility to the Development of Schizophrenia

“…Schizophrenia is a disabling mental disorder that stands out due to the high prevalence rate, besides the high economic cost generated in the treatment of these patients (Daltio et al, 2007). This severe psychotic disorder affects about 1% of the world population and is characterized by the presence of symptoms called psychotic, or positive (hallucinations, delusions and disturbances of thoughts and movements), negative symptoms (affective insensitivity, speech loss and anhedonia) and cognitive impairment.…”

“…According to OS and Marcelis (1998), schizophrenia is a multifactorial disease and may be associated with environmental (prenatal and perinatal complications, drug use, life events) and genetic factors (Van OS;Marcelis, 1998). Studies show that the chances of developing the disease are much higher in individuals who have first-degree relatives with schizophrenia, reaching about 10% of these individuals and 50% in cases of identical twins (Cardno;Gottesman, 2000;Castellani et al, 2017). Studies of broad genomic association identified more than 100 loci related to the susceptibility of the individual to the disease, among them the genes CNTN4, GATAD2A, GPM6A, MMP16, PSMA4, TCF4, ZNF804A, DRD4 ( Xu, Wu, Zhang, Wang & Yao, 2018;Kuswanto et al, 2012;Ma et al, 2018).…”