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

Abstract

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.

Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response

“…Rs228697 in PER3 has been linked to morningness–eveningness preference and circadian rhythm sleep disorders, although the length polymorphism/VNTR in PER3 has been linked to stress response and bipolar disorder.. 26 , 27 , 28 In addition, rs12137927 (the same SNP implicated in our study) and rs228644 from PER3 and rs11632098 from RORA were reportedly linked to endorsing the presence of both a modest number (>2 to <6) and a high number of depressive symptoms (⩾6) on the Geriatric Depression Scale as compared with endorsing none-few depressive symptoms (0–2). 29 The variant with association signal of P <0.0001 in the NR1D1 interval is variant rs10305315, located downstream of IGFBP4 ( P =5.99 × 10 −5 ). It remains unclear whether rs10305315 affects the function of NR1D1 (no eQTL evidence from GTEx portal based on GTEx Analysis Release V6).…”

Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

“…Most importantly, by inhibiting ROR γ transcriptional activity and thereby reducing Th17 generation and IL-17A/F production, ROR γ inverse agonists may provide a novel strategy in the treatment of various pathologies in which ROR γ is implicated, including inflammatory, metabolic, endocrine, and autoimmune diseases [ 1 , 2 , 13 , 25 , 257 , 258 ]. Similarly, ROR α antagonists might affect pathologies by inhibiting the generation of ILC2 cells and other physiological functions and be useful in the management of inflammatory, metabolic, and neuropsychiatric disorders [ 1 , 2 , 13 , 25 , 108 , 113 – 117 , 174 ]. This concept is supported by reports showing that by inhibiting Th17 differentiation and IL-17 production, ROR γ inverse agonists suppress Th17 responses in mice and ameliorate the development of experimental autoimmune encephalomyelitis and imiquimod-induced cutaneous inflammation [ 43 , 244 , 246 , 259 ].…”

“…Clinical studies have indicated an important association between abnormalities in circadian rhythms and patients with mood and neuropsychiatric disorders. Alterations in circadian behavior observed in mice deficient in either ROR α or ROR β receptor [ 122 , 124 , 216 ] and associations between SNPs in RORA and RORB with an increased risk for several neuropsychiatric disorders, including autism spectrum (ASD) and bipolar disorder, schizophrenia, depression, and posttraumatic stress syndrome [ 106 – 117 , 129 , 130 ], would be consistent with a link between disturbance in the circadian rhythm and these pathologies.…”

“…Accumulating evidence indicates a role for ROR α in several neuropsychiatric disorders, including autism spectrum and bipolar disorder (ASD), schizophrenia, depression, and posttraumatic stress syndrome [ 106 – 117 ]. Studies demonstrating that the expression of RORA was reduced in sections of cerebellum and cortex of autistic subjects and observations showing differential methylation of the RORA gene in lymphoblastoid cells from autistic and nonautistic siblings supported a role of ROR α in the development of ASD [ 107 ].…”

Chronobiology Revisited in Psychiatric Disorders: From a Translational Perspective

“…Compete with RORA for binding to the BMAL-1 promoter and repress the BMAL-1 MDD (Soria et al, 2010;Byrne et al, 2014) BD (Kishi et al, 2008;Kripke et al, 2009;Severino et al, 2009) Rora Retinoid-related orphan receptor a (RORA) Works as nuclear hormone receptors. Compete with NR1D1 for binding to the BMAL-1 promoter and activate the BMAL-1 MDD Utge et al, 2010;Maglione et al, 2015) BD Lai et al, 2015;Geoffroy et al, 2016 (Kupfer and Foster, 1972;Kupfer, 1976;Rush et al, 1986;Giles et al, 1987;Pillai, Kalmbach and Ciesla, 2011) BD Euthymia; Increased REM density and proportion of REM sleep, longer sleep onset latency and sleep duration, lower sleep efficiency (Sitaram et al, 1982;Millar, Espie and Scott, 2004;Rocha, Neves and Corrêa, 2013;Geoffroy et al, 2015) Mania; Shortened REM sleep latency, increased REM activity and REM density, reduced total sleep time (Hudson et al, 1988(Hudson et al, , 1992Linkowski and Mendlewicz, 1993) Depression; More fragmented REM sleep periods, shortened REM sleep latency (Gillin et al, 1979;Lauer, Wiegand and Krieg, 1992) longer sleep onset latency, increased proportion of REM sleep, trend toward higher percentage of awakenings in bipolar depression than in unipolar depression (Giles, Rush and Roffwarg, 1986;Jernajczyk, 1986;Fossion et al, 1998)…”