Obstetric Complications, Genetic Liability and Psychosis

: A study of Gene X Environment Interaction

Abstract

There is no doubt a strong genetic component to psychosis, but family and twin studies have shown that simple genetic transmission is far from the whole story. Furthermore, a number of environmental factors have also been shown to increase risk of psychosis. Among these non genetic causes, Obstetric Complications (OCs) are among the best replicated.

In order to get a better insight into the mechanisms by which OCs impact on brain development to increase the risk of psychosis, I employed a Gene X Environment causation model.

A total of 377 psychotic patients, 65 controls and 103 unaffected siblings were available for my project. I obtained data concerning clinical and socio-demographic status, obstetric history, together with samples of blood/cheek swabs for genetic analysis from these subjects. I also genotyped most of the subjects (N=399) for selected genetic variants that might have functional significance in relation to the individual’s exposure to OCs (namely AKT1 rs 2494753, rs1130233, rs3803300; BDNF rs2049046, rs56164415; DNMBP1 rs875462; GRM3 rs7808623; AK573765- TWIST2 rs9751357; CACNA1C rs4765905; CEACAM21 rs4803480; CNNM2 rs7914558; CSMD1 rs10503253; Erbb4 rs1851196; ITIH3/4 rs2239547; LOC645434-NMBR rs2066036; LRRFIP1 rs12052937; MIR137 rs1625579; MMP16 rs7004633; NKAPL rs1635; NRG rs12807809; NT5C2 rs11191580; PCLO rs6979348; PLXNA2 rs752016; PGBD1 rs2142731; PCGEM1 rs17662626; RELN rs7341475; SDCCAG8 rs6703335; STT3A rs548181; TCF4 rs17512836; UGT1A1 HJURP rs741160; rs10489202; rs16887244).

In a case-control design, I investigated how exposure to OCs influenced the risk of psychotic disorder.

Then, I tested, under a multiplicative model, the hypothesis that a range of genetic variants interacted with OCs in increasing the risk of psychotic disorder.

Lastly I examined whether rats that had experienced perinatal asphyxia during birth
show abnormalities in gene expression and methylation status at various
developmental periods.

My findings didn’t show any interaction between genes and OCs in increasing the risk of psychosis. On the other hand, in rats following hypoxic insult many of the genes had heterogeneous pattern of expression, suggesting an important role for genes in mediating the reactions of the CNS to environmental stimuli such hypoxia. In general, at post neonatal day CNNM2 was down regulated, whereas CSMD1 and TCF4 were up regulated; at 5 weeks CNNM2, CSMD1, MMP16, STT3a were down regulated, whereas TRIM26 was overexpressed. Hypoxia in the prenatal and perinatal period could regulate the expression of specific genes contributing to the neurodevelopmental alterations later found in schizophrenic patient.

Date of Award	2014
Original language	English
Awarding Institution	King's College London
Supervisor	Robin Murray (Supervisor) & John Powell (Supervisor)