Abstract
Depression is a severe and debilitating mental disorder diagnosed by evaluation of affective, cognitive and physical depression symptoms. Severity of these symptoms strongly impacts individual’s quality of life and is influenced by a combination of genetic and environmental factors. One of the molecular mechanisms allowing for an interplay between these factors is DNA methylation, an epigenetic modification playing a pivotal role in regulation of brain functioning across lifespan. The aim of this study was to investigate if there are DNA methylation signatures associated with depression symptomatology in order to identify molecular mechanisms contributing to pathophysiology of depression. We performed an epigenome-wide association study (EWAS) of continuous depression symptomatology score measured in a cohort of 724 monozygotic Danish twins (346 males, 378 females). Through EWAS analyses adjusted for sex, age, flow-cytometry based blood cell composition, and twin relatedness structure in the data we identified depression symptomatology score to be associated with blood DNA methylation levels in promoter regions of neuropsin (KLK8, p-value = 4.7 × 10−7) and DAZ associated protein 2 (DAZAP2, p-value = 3.13 × 10−8) genes. Other top associated probes were located in gene bodies of MAD1L1 (p-value = 5.16 × 10−6), SLC29A2 (p-value = 6.15 × 10−6) and AKT1 (p-value = 4.47 × 10−6), all genes associated before with development of depression. Additionally, the following three measures (a) DNAmAge (calculated with Horvath and Hannum epigenetic clock estimators) adjusted for chronological age, (b) difference between DNAmAge and chronological age, and (c) DNAmAge acceleration were not associated with depression symptomatology score in our cohort. In conclusion, our data suggests that depression symptomatology score is associated with DNA methylation levels of genes implicated in response to stress, depressive-like behaviors, and recurrent depression in patients, but not with global DNA methylation changes across the genome.
Highlights
Depression is a multifactorial common psychiatric disorder diagnosed by evaluation of various depressive symptoms, such as low mood, loss of interest and pleasure, fatigue and loss of energy, decline in cognitive functioning, poor concentration, increase in anxiety, inappropriate guilt, change in appetite, sleep disturbance, as well as changes in psychomotor activity[1]
Results from paired and unpaired epigenome-wide association study (EWAS) of depression symptomatology obtained from Middle Aged Danish Twin Study (MADT) and Longitudinal Study of Aging in Danish Twins (LSADT) monozygotic twin cohorts were further used to identify possible differentially methylated regions (DMRs) across the genome associated with this trait
Five genes overlapped between DMR paired and unpaired analysis (PCDHGA4, GLIPR1L2, STAM, VARS2, MAST3), 2 genes overlapped between paired EWAS and paired DMR analysis (MAD1L1 and RGS12), and 1 gene overlapped between paired EWAS and unpaired DMR analysis (ATF6B)
Summary
Depression is a multifactorial common psychiatric disorder diagnosed by evaluation of various depressive symptoms, such as low mood, loss of interest and pleasure, fatigue and loss of energy, decline in cognitive functioning, poor concentration, increase in anxiety, inappropriate guilt, change in appetite, sleep disturbance, as well as changes in psychomotor activity[1]. Due to the complexity of depression symptomatology and its varying severity across the general population, depression is reported to be under-diagnosed and under-treated in society[3,4,5]. Depression is estimated to be the leading global cause of years lost due to disability worldwide, with lifetime prevalence of the disorder estimated to be ~14%, and even reaching 21% in high-income countries[6,7]. Apart from genetic factors, which contribute to but do not fully explain individual’s disorder risk, environmental exposures, such as social and socioeconomic factors (social isolation[15], life events[16], low income or financial problems[17], level of education18,19), as well as lifestyle factors (such as diet[20] or level of physical activity21) impact severity of depression symptomatology and risk of developing depression across the lifespan[22]
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