Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide and a major contributor to early mortality from suicide. It is a common psychiatric illness with a wellestablished heritability. MDD is an extremely heterogeneous disorder in terms of symptoms, genetics and environmental risk factors. This thesis uses genetic and environmental data from case-control, clinical trial and population samples to dissect the heterogeneity of MDD.Gene-environment interactions were tested in the Radiant UK recurrent depression sample using polygenic risk scores (PRS), which reflect genetic liability for MDD based on many common variants. No interactions were found between PRS and adult adverse events. Interactions between PRS and childhood trauma showed an inverse association with MDD status, as cases who experienced more severe trauma tended to have a lower PRS.
The current selection pressures on genetic variants associated with MDD and other psychiatric disorders were investigated in the Icelandic population by testing whether PRS are associated with number of offspring. There was no evidence that risk alleles for depression are under selection, whereas higher PRS for autism were associated with fewer children and higher PRS for ADHD were associated with having more children.
Genome-wide association studies on suicide attempt were conducted comparing 6,569 attempters versus 17,232 non-attempters from MDD, bipolar disorder and schizophrenia cases in the Psychiatric Genomics Consortium. This identified three genome-wide significant loci for suicide attempt in mood disorders, which will be replicated in independent samples. Finally, blood mRNA levels of SAT1, PTEN, MAP3K3 and MARCKS have been reported as biomarkers for suicidality and here, an independent test in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study did not support the validity of the proposed biomarkers. The availability of phenotypic, genetic and environmental data provides abundant opportunities to leverage the heterogeneity of depression to better understand its complex aetiology.
| Date of Award | 2017 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Cathryn Lewis (Supervisor) & Gerome Breen (Supervisor) |