Mdical Diseases and Obesity in Major Depressive Disorder

Abstract

The association between major depressive disorder (MDD) and various physical diseases is well recognized. However, previous studies have mainly focused on depression in physically ill individuals. My thesis aims to investigate the reverse direction, i.e. the occurrence of physical diseases including obesity in individuals with MDD. First, I found evidence for higher prevalence rates for eight out of the 16 common physical diseases studied here in depressed people compared to controls with no history of MDD. Affected and unaffected siblings of the depressed subjects showed a similar pattern. The diseases that were significantly more common in depressed subjects were hypertension, hypercholesterolemia, myocardial infarction, asthma, allergic rhinitis/ hay fever, gastric ulcer, osteoarthritis and thyroid disease. In addition, factor and correlational analyses showed that groups of physical diseases tended to cluster together in families where one or more individuals suffered from depression. The most striking of these was a ‘metabolic syndrome’ cluster, which was associated with high body mass index (BMI). Second, I explored personality factors as possible mediators of the link between MDD and physical diseases. Neuroticism, as measured by the Eysenck Personality Questionnaire, was associated with an increased number of self-reported physical diseases in individuals with MDD. Among individual diseases, only asthma had a modest but significant association with MDD. However, we did not find a familial correlation between neuroticism and asthma, suggesting that the phenotypic association between neuroticism and asthma is unlikely to have a genetic component. Third, a new statistical tool was used to estimate the proportion of phenotypic variance of complex diseases/ traits that can be explained by common tag single nucleotide polymorphisms (SNPs), termed “SNP heritability”. Analysis indicated that a substantial proportion of phenotype variance of both BMI and MDD was explained by common genetic variants. There was also suggestive evidence for a substantial genetic correlation between BMI and MDD, although the estimates had large standard errors. This imprecision almost certainly reflects the fact that, although the samples used here were large, even greater sample sizes are required for analyses of SNP heritability. Fourth, I used 32 SNPs identified from a published meta-analysis of genome-wide association studies (GWAS) on BMI to construct both weighted and un-weighted genetic risk scores (GRS) for BMI. Perhaps surprisingly, only 1.27% of the variance of BMI score was explained by the GRSs derived from these SNPs. Subsequent analyses showed that neither GRS alone, nor GRS combined with ‘traditional’ risk factors, can provide, in our present state of knowledge, a useful tool to discriminate the presence or absence of obesity in depressed people. Fifth, Mendelian randomization (MR) was used to attempt to disentangle the causal relationship between increased BMI and MDD. Although conventional regression analysis suggested a strong association between increased BMI and MDD, MR analysis failed to support the hypothesis that increased BMI is a causal factor in the development of MDD. Finally, I further explored the association between MDD and physical diseases by reviewing published genome wide association study (GWAS) data on MDD to examine whether identified risk loci for MDD overlapped with loci implicated in physical diseases. I then analysed our own GWAS data on depression to examine the presence of case/control differences at loci where there had been physical disease ‘hits’ in published studies. Analyses indicated that the SNP rs1342326, near the IL33 gene, which was genome-wide significant in a GWAS on asthma, was over-represented in individuals with MDD. However, MR analysis did not support a causal relationship between suffering from asthma and
having MDD. These results could suggest a single point of genetic overlap between asthma and MDD that might contribute to the observed phenotypic overlap between the two disorders, and highlight the need for further studies in larger samples.
In summary, the analyses presented in this thesis show that the relationship between MDD and physical diseases/ obesity is complicated, but suggests that genetic factors play a role in the overlap between depression and BMI and, by implication, diseases associated with high BMI. Only one non-BMI associated disease, asthma, has an identifiable polymorphism that is also associated with depression and withstands correction for multiple testing. Further larger scale studies searching for disease associated variants are vital in order to understand the pathogenesis of the co-occurrence between MDD and physical diseases/ obesity. These will include genome-wide and, eventually, deep sequencing studies of very large cohorts such as the UK Biobank.

Date of Award	2015
Original language	English
Awarding Institution	King's College London
Supervisor	Peter McGuffin (Supervisor), Gerome Breen (Supervisor) & Oliver Davis (Supervisor)