Abstract
BackgroundThere are several indications that malfunctions of the circadian clock contribute to depression. To search for particular circadian gene polymorphisms associated with depression, diverse polymorphisms were genotyped in two samples covering a range of depressed volunteers and participants with normal mood.MethodsDepression mood self-ratings and DNA were collected independently from a sample of patients presenting to a sleep disorders center (1086 of European origin) and from a separate sample consisting of 399 participants claiming delayed sleep phase symptoms and 406 partly-matched controls. A custom Illumina Golden Gate array of 768 selected single nucleotide polymorphisms (SNPs) was assayed in both samples, supplemented by additional SNPlex and Taqman assays, including assay of 41 ancestry-associated markers (AIMs) to control stratification.ResultsIn the Sleep Clinic sample, these assays yielded Bonferroni-significant association with depressed mood in three linked SNPs of the gene FMR1: rs25702 (nominal P=1.77E-05), rs25714 (P=1.83E-05), and rs28900 (P=5.24E-05). This FMR1 association was supported by 8 SNPs with nominal significance and a nominally-significant gene-wise set test. There was no association of depressed mood with FMR1 in the delayed sleep phase case–control sample or in downloaded GWAS data from the GenRED 2 sample contrasting an early-onset recurrent depression sample with controls. No replication was located in other GWAS studies of depression. Our data did weakly replicate a previously-reported association of depression with PPARGC1B rs7732671 (P=0.0235). Suggestive associations not meeting strict criteria for multiple testing and replication were found with GSK3B, NPAS2, RORA, PER3, CRY1, MTNR1A and NR1D1. Notably, 16 SNPs nominally associated with depressed mood (14 in GSK3B) were also nominally associated with delayed sleep phase syndrome (P=3E10-6).ConclusionsConsidering the inconsistencies between samples and the likelihood that the significant three FMR1 SNPs might be linked to complex polymorphisms more functionally related to depression, large gene resequencing studies may be needed to clarify the import for depression of these circadian genes.
Highlights
There are several indications that malfunctions of the circadian clock contribute to depression
Clock-controlled oscillation is influenced by transcription factors such as the Clock circadian regulator [HGNC (CLOCK)-Aryl hydrocarbon receptor nuclear translocator-like [HGNC (ARNTL)-CRY-Period [GenBank (PER) complex binding at E-box sites, by Nuclear receptor subfamily 1 (NR1D1), Nuclear receptor subfamily 1 (NR1D2), and RAR-related orphan receptor A [HGNC (RORA) and homologues interacting at RevErbA/ROR binding element (RRE) sites, by DBP and homologues binding with DBP/E4BP4 binding element (D-box) sites, by kinases influencing clock component proteins, and by circadian control of energy metabolism [8], to give examples of an extremely complex network [9,10]
The functional plausibility of an Fragile X mental retardation 1 [HGNC (FMR1) association with depression is supported by its position on the nonautosomal X chromosome, by reports of fragile X premutation carriers being susceptible to depression [20,21,22,23,24], by well-known effects of FMR1 on brain synaptic functions [18,19], and by the interesting nominallysignificant association in Fragile X mental retardation (FXR2) rs7211847, P=0.0165 in Sleep Clinic and delayed sleep phase syndrome (DSPS) samples meta-analysis)
Summary
There are several indications that malfunctions of the circadian clock contribute to depression. Core clock genes and clock-controlled genes are significantly associated with bipolar disorder, with lithium response, and to some extent with unipolar depression, though the association of individual genes does not rise to conventional criteria for genome-wide association [11]. These significant associations appear to support the overall hypothesis that the circadian genetic system is involved in depression, implying an influence of combinations of numerous polymorphisms in complex genetic pathways
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