FMR1, circadian genes and depression

Suggestive associations or false discovery?

Daniel F. Kripke, Caroline M. Nievergelt, Gregory J. Tranah, Sarah S. Murray, Katharine M. Rex, Alexandra P. Grizas, Elizabeth K. Hahn, Heon-Jeong Lee, John R. Kelsoe, Lawrence E. Kline

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: There 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.Methods: Depression 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.Results: In 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).Conclusions: Considering 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.

Original languageEnglish
Article number3
JournalJournal of Circadian Rhythms
Volume11
Issue number1
DOIs
Publication statusPublished - 2013 Mar 23

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Depression
Single Nucleotide Polymorphism
Genes
Sleep
Genome-Wide Association Study
Circadian Rhythm Sleep Disorders
Circadian Clocks
Volunteers
DNA

Keywords

  • Circadian
  • Depression
  • DSPS
  • FMR1
  • GSK3B
  • NR1D1
  • PPARGC1B
  • rs25702
  • rs28900
  • rs7732671

ASJC Scopus subject areas

  • Physiology
  • Endocrine and Autonomic Systems

Cite this

Kripke, D. F., Nievergelt, C. M., Tranah, G. J., Murray, S. S., Rex, K. M., Grizas, A. P., ... Kline, L. E. (2013). FMR1, circadian genes and depression: Suggestive associations or false discovery? Journal of Circadian Rhythms, 11(1), [3]. https://doi.org/10.1186/1740-3391-11-3

FMR1, circadian genes and depression : Suggestive associations or false discovery? / Kripke, Daniel F.; Nievergelt, Caroline M.; Tranah, Gregory J.; Murray, Sarah S.; Rex, Katharine M.; Grizas, Alexandra P.; Hahn, Elizabeth K.; Lee, Heon-Jeong; Kelsoe, John R.; Kline, Lawrence E.

In: Journal of Circadian Rhythms, Vol. 11, No. 1, 3, 23.03.2013.

Research output: Contribution to journalArticle

Kripke, DF, Nievergelt, CM, Tranah, GJ, Murray, SS, Rex, KM, Grizas, AP, Hahn, EK, Lee, H-J, Kelsoe, JR & Kline, LE 2013, 'FMR1, circadian genes and depression: Suggestive associations or false discovery?', Journal of Circadian Rhythms, vol. 11, no. 1, 3. https://doi.org/10.1186/1740-3391-11-3
Kripke DF, Nievergelt CM, Tranah GJ, Murray SS, Rex KM, Grizas AP et al. FMR1, circadian genes and depression: Suggestive associations or false discovery? Journal of Circadian Rhythms. 2013 Mar 23;11(1). 3. https://doi.org/10.1186/1740-3391-11-3
Kripke, Daniel F. ; Nievergelt, Caroline M. ; Tranah, Gregory J. ; Murray, Sarah S. ; Rex, Katharine M. ; Grizas, Alexandra P. ; Hahn, Elizabeth K. ; Lee, Heon-Jeong ; Kelsoe, John R. ; Kline, Lawrence E. / FMR1, circadian genes and depression : Suggestive associations or false discovery?. In: Journal of Circadian Rhythms. 2013 ; Vol. 11, No. 1.
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abstract = "Background: There 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.Methods: Depression 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.Results: In 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).Conclusions: Considering 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.",
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AU - Rex, Katharine M.

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N2 - Background: There 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.Methods: Depression 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.Results: In 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).Conclusions: Considering 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.

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