| dc.description.abstract | AIMS:
Depression is a common mental disorder and the leading cause of disability
world-wide (GBD 2018). With heritability measures around 37%
(Sullivan, Neale, & Kendler, 2000), most of the risk for developing depression is of a
likely environmental origin. Socioeconomic status has been repeatedly associated with
depression and its many comorbid diseases (Gold et al., 2020) in studies that differ
widely in their age range and geographical coverage. As a result, estimates of
depression risk stratified by SES are imprecise and not easily generalisable. The
biological mechanisms underlying the association between SES and depression are
similarly poorly understood, although differences in alcohol consumption, smoking
behaviour, and obesity are widely reported. Inflammatory mechanisms have also been
implicated in both SES and depression.
The aim of this thesis is to establish whether SES is associated with depression
using the broadest possible evidence-base, to provide an estimate of depression risk
linked to low SES, and to explore it’s underlying biological mechanisms.
METHODS:
I conducted a systematic review and meta-analysis of studies investigating the
association between clinical depression and SES. There were no restrictions on
country of origin, age of participants or publication date. The 140 included studies (N
= 329,005, N of cases = 48,158) were meta-analysed (dichotomised into low and high
SES) and reviewed, and gross national income per capita was used to interrogate
differences in risk estimates and between-study heterogeneity.
To investigate the biological mechanisms associated with low SES I performed
a methylome wide association study (MWAS) on the Scottish Index of Multiple
Deprivation (SIMD, a continuous measure) using the single largest DNA methylation
(DNAm) dataset, Generation Scotland. Estimates from the SIMD MWAS were used to
predict Index of Multiple Deprivation (IMD) in the Avon Longitudinal Study of
Parents and Children (ALSPAC) as a replication analysis.
I then performed an MWAS on the interaction of inflammatory disease and
depression to further interrogate the findings from the SIMD MWAS and connect
these findings to a possible low-SES subtype of depression. For both MWASs I
performed differentially methylated point (DMP) and region (DMR) analysis,
functional mapping and annotation of the differentially methylated genes, and gene set
enrichment analysis.
RESULTS:
The systematic review and meta-analysis revealed an increased risk of
depression associated with low SES (odds ratios from 1.57 to 1.95). The results were
consistent across cultures, and SES measures. Low income was associated with the
highest risk of depression. There was considerable between study effect size
heterogeneity (I2 = 81-87%) in almost all meta-analysed outcomes.
The MWAS of SIMD returned 15 epigenome wide significant DMPs, and 449
DMRs. Functional annotation and gene enrichment analysis revealed bone health,
cardiovascular diseases, inflammatory diseases, and major depression as associated
phenotypes.
The inflammatory depression MWAS showed no epigenome wide significant
DMP but 8 DMPs reached a less rigorous ‘discovery threshold’ and 7 epigenome wide
significant DMRs were found. Genetic functional annotation and gene enrichment
analysis implicated inflammatory markers, inflammatory diseases, response to SSRIs,
liver and kidney function, and gluconeogenic pathways.
CONCLUSION:
Findings from this thesis show that low SES and risk of clinical depression are
positively associated. Longitudinal studies hint at a low SES to MDD direction of
causality, but the evidence is only suggestive, and it is likely to be a bidirectional
relationship. Low SES is associated with many physical measures and conditions even
after accounting for smoking, alcohol consumption, and BMI. Low SES is associated
with a range of inflammatory markers and chronic mental and physical diseases. The
biological mechanisms underlying the link between SES and depression may be
related to systemic chronic inflammation. Possible sources for this systemic
inflammation include several frequently comorbid chronic health problems and
environmental toxins. These findings provide further impetus to investigate the
mechanisms underlying the depression-SES association and develop interventions to
mitigate the many health risks associated with low SES. | en |
