Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, similar to 10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated

Genetic variants in RBFOX3 are associated with sleep latency

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10-08, 6.59 × 10- 08 and 9.17 × 10- 08). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10- 02, 7.0 × 10- 03 and 2.5 × 10- 03; combined meta-analysis P-values=5.5 × 10-07, 5.4 × 10-07 and 1.0 × 10-07). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10-316) and the central nervous system (P-value=7.5 × 10- 321). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitte

Adolescent suicidal ideation: a comparison of incarcerated and school-based samples

and risk-taking behavior. RESULTS: Suicidal ideations during the past year were reported by 21.5% of detained males, compared to 6.7% in the general population. In females, 58.1% of detained individuals reported suicidal thoughts during the past year, compared to 14.4% of the general population. In girls and boys from the general population, both internalizing and externalizing problems were higher in suicidal ideators than in non-suicidal youth, while in the detention group mainly internalizing problems were higher in suicidal ideators. When comparing detention suicidal ideators with those from the general population, male suicidal ideators scored higher on delinquency, while detained female suicidal ideators also scored higher on posttraumatic stress, but lower on prosocial beliefs. LIMITATIONS: Information used in this study was solely based on self-report measures only and limited to Flemish adolescents. CONCLUSION: Since suicidal ideation is a frequent problem in detained youth, adequate recognition and treatment seems clinically relevant. While both internalizing and externalizing psychopathology may be an indicator of suicidal ideation in the general population, internalizing problems may be the main clinical predictor in detained yout

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI

Sleep disturbances and reduced work functioning in depressive or anxiety disorders

<p>Objectives: We aimed to examine the associations between sleep disturbances and work functioning in an epidemiologic cohort study in subjects with or without depressive or anxiety disorders.</p><p>Methods: There were 707 subjects included in our analyses with depressive or anxiety disorders and 728 subjects without current depressive or anxiety disorders. Insomnia was defined as a score >= 9 using the Insomnia Rating Scale. Self-reported sleep duration was categorized in short, normal, and long (= 10 h, respectively). Work absenteeism was defined as none, short (2 weeks). Work performance was defined as not impaired, reduced, or impaired. Logistic regression analyses were performed to examine the associations of sleep disturbances with work functioning.</p><p>Results: In subjects with psychopathology, insomnia and short sleep duration were significantly associated with impaired work performance (odds ratio [OR] for insomnia, 2.20; [95% confidence interval {CI}, 1.50-3.22]; OR for short sleep, 2.54 [95% CI, 1.66-3.88] compared to normal sleep duration). Insomnia (OR, 2.48 [95% CI, 1.67-3.69]) and short sleep duration (OR, 1.85 [95% CI, 1.23-2.78]) also were associated with long-term absenteeism. These findings remained the same after considering clinical characteristics including medication use and symptom severity. Results: In subjects without psychopathology, no significant associations were found between insomnia and short sleep duration on work functioning after considering subthreshold depression symptoms.</p><p>Conclusions: In subjects with psychopathology, sleep disturbances were negatively associated with work functioning, independent of disorder severity and use of psychotropic medication. Further research is needed to determine if treatment of sleep disturbances in subjects with psychopathology improves work functioning. (C) 2013 Elsevier B.V. All rights reserved.</p>

<特集1>阪神・淡路大震災 第1部 活動のまとめ

OBJECTIVE: To examine the predictive role of insomnia and sleep duration on the 2-year course of depressive and anxiety disorders. METHOD: This study is a secondary data analysis based on data from the baseline (2004-2007) and 2-year assessment of the Netherlands Study of Depression and Anxiety. Participants were 1,069 individuals with DSM-IV-based depressive and/or anxiety disorders at baseline. Sleep measures included insomnia (Women's Health Initiative Insomnia Rating Scale score ≥ 9) and sleep duration (categorized as short [≤ 6 hours], normal [7-9 hours], or long [≥ 10 hours]). Outcome measures were persistence of DSM-IV depressive and anxiety disorders (current diagnosis at 2-year follow-up), time to remission, and clinical course trajectory of symptoms (early sustained remission, late remission/recurrence, and chronic course). Logistic regression analyses were adjusted for sociodemographic characteristics and chronic medical disorders, psychotropic medications, and severity of depressive and anxiety symptoms. RESULTS: The effect of insomnia on persistence of depressive and/or anxiety disorders (OR = 1.50; 95% CI, 1.16-1.94) was explained by severity of baseline depressive/anxiety symptoms (adjusted OR with severity = 1.04; 95% CI, 0.79-1.37). Long sleep duration was independently associated with persistence of depression/anxiety even after adjusting for severity of psychiatric symptoms (OR = 2.52; 95% CI, 1.27-4.99). For short sleep duration, the independent association with persistence of combined depression/anxiety showed a trend toward significance (OR = 1.32; 95% CI, 0.98-1.78), and a significant association for the persistence of depressive disorders (OR = 1.49; 95% CI, 1.11-2.00). Both short and long sleep duration were independently associated with a chronic course trajectory (short sleep: OR = 1.50; 95% CI, 1.04-2.16; long sleep: OR = 2.91, 95% CI, 1.22-6.93). DISCUSSION: Both short and long sleep duration-but not insomnia-are important predictors of a chronic course, independent of symptom severity. It is to be determined whether treating these sleep conditions results in more favorable outcomes of depression and anxiety

Genetic variants in RBFOX3 are associated with sleep latency

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-value

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated