FMR1, circadian genes and depression: suggestive associations or false discovery?

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

doi:10.1186/1740-3391-11-3

Cited by 11 publications

(16 citation statements)

References 70 publications

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“…There were 13 Bonferroni-significant associations of SNPS with 11 phenotypes, which are presented in Table 1 . This included three SNPs of the fragile X mental retardation 1 ( FMR1 ) gene associated with a reduced QIDS-SR depression self-rating, which have been discussed in more detail elsewhere [ 36 ], but a somewhat different statistical model is presented here to provide perspective and comparison. Additional Bonferroni-significant results were as follows.…”

Section: Resultsmentioning

confidence: 99%

Genetic variants associated with sleep disorders

et al. 2015

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Objective The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. Methods Patients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance. Results In peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep. Conclusions SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

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Section: Resultsmentioning

confidence: 99%

Genetic variants associated with sleep disorders

et al. 2015

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“…Studies have reported significant associations between PER3 variants and mood disorder characteristics such as age of onset, response to pharmacotherapy, and circadian mood oscillations (23, 56, 57). Other studies found only suggestive associations (58, 59), or no significant associations (26). Associations between circadian gene polymorphisms and subthreshold levels of depressive symptoms have not previously been reported in older adults.…”

Section: Discussionmentioning

confidence: 90%

Associations of PER3 and RORA Circadian Gene Polymorphisms and Depressive Symptoms in Older Adults

Maglione

Nievergelt

Parimi

et al. 2015

The American Journal of Geriatric Psychiatry

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Background Depressive symptoms are common in older adults and associated with poor outcomes. While circadian genes have been implicated in depression, the relationship between circadian genes and depressive symptoms in older adults is unclear. Methods A cross-sectional genetic association study of 529 single nucleotide polymorphisms (SNPs) representing 30 candidate circadian genes was performed in two population-based cohorts: Osteoporotic Fractures in Men Study (MrOS, n=1270, age 76.58±5.61 years) and the Study of Osteoporotic Fractures (SOF) in women (n=1740, 84.05±3.53 years) and a meta-analysis was performed. Depressive symptoms were assessed with the Geriatric Depression Scale categorizing participants as having “none-few symptoms” (0-2), “some depressive symptoms” (>2<6), or “many depressive symptoms” (≥6). Results We found associations meeting multiple testing criteria for significance between the PER3 intronic SNP rs12137927 and decreased odds of reporting “some depressive symptoms” in the SOF sample (OR 0.61, CI 0.48-0.78, df=1, Wald chi-square −4.04, p=0.000054) and the meta-analysis (OR 0.61, CI 0.48-0.78, z= −4.04, p=0.000054) and between the PER3 intronic SNPs rs228644 (OR 0.74, CI 0.63-0.86, z= 3.82, p-value=0.00013) and rs228682 (OR 0.74, CI 0.86 0.63, z= 3.81, p-value=0.00014) and decreased odds of reporting “some depressive symptoms” in the meta-analysis compared to endorsing none-few depressive symptoms. The RORA intronic SNP rs11632098 was associated with greater odds of reporting “many depressive symptoms” (OR 2.16, CI 1.45-3.23, df=1, Wald chi-square 3.76, p=0.000168) in the men. In the meta analysis the association was attenuated and nominally significant (OR 1.63, CI 1.24-2.16, z=3.45, p=0.00056). Conclusions PER3 and RORA may play important roles in the development of depressive symptoms in older adults.

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“…To best recognize a DSPS phenotype, those receiving a diagnostic code 327.31 or having BALM score <28 were classified as DSPS phenotype, a BALM <28 being suggested by our previous study 30. This was a more liberal BALM criterion than that used in our examination of pleiotropy with depression 34. Those patients not meeting DSPS criteria were utilized as controls.…”

Section: Methodsmentioning

confidence: 99%

“…The BALM alternate criterion was needed because clinicians sometimes omitted making a DSPS diagnosis when the primary diagnostic focus was sleep apnea, Willis-Ekbom disease, etc. Having studied the data further, we used this looser BALM criterion for DSPS yielding almost twice as many DSPS cases as in of our previous report on the same data wherein the BALM criterion used was 23 34. It was surprising that the change in criteria made substantial alterations in which SNPs were nominally associated with DSPS in the Sleep Center sample, particularly reducing the nominal association of GSK3B SNPs.…”

Section: Methodsmentioning

confidence: 99%

Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles

Kripke

Klimecki

Nievergelt

et al. 2014

Psychiatry Investig

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People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness-eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.

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FMR1, circadian genes and depression: suggestive associations or false discovery?

Cited by 11 publications

References 70 publications

Genetic variants associated with sleep disorders

Genetic variants associated with sleep disorders

Associations of PER3 and RORA Circadian Gene Polymorphisms and Depressive Symptoms in Older Adults

Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles

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