Genes for height have gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in ...approximately 4000 individuals from five European populations. A total of five chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal P = 7.0 × 10−8 and P = 9.6 × 10−7, respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal P < 1.6 × 10−7). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (n = 31 077, n=1268 and n = 5746) with overall meta P-values of 9.4 × 10−10 and 5.3 × 10−8. These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycemia and growth retardation when knocked out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height identified so far.
As major risk-factors for diabetes and cardiovascular diseases, the genetic contribution to obesity-related traits has been of interest for decades. Recently, a limited number of common genetic ...variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome-wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome-wide level (nominal P < 1.6 × 10(−7), Bonferroni-adjusted P < 0.05) one single-nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 × 10(−8)) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women.
ABSTRACT
To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID‐associated genes ...using targeted next‐generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss‐of‐function LoF variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%–15% yield from array CGH alone.
For diseases caused by high new mutation rates e.g. intellectual disability, the availability of DNA from both parents for trio analysis is invaluable. However, in single parent households, a loss of function variant analysis of a panel of known disease‐causing genes plus analysis of a limited list of previously established pathogenic missense variants can yield a diagnostic rate of 11%. This strategy has significant clinical utility where samples from both parents are unavailable.
Abstract Introduction Insomnia, chronic pain, and stress are highly comorbid, contributing to significant distress and impairment. Research on measures of insomnia, such as the Insomnia Severity ...Index, have revealed a two-factor structure consisting of both severity of insomnia symptoms and perceived distress and impairment. Prior research suggests that this perceived distress and impairment factor may represent a cognitive vulnerability that may impact other domains, including experiences of pain and stress. Pain catastrophizing, “a negative cognitive–affective response to anticipated or actual pain” and sleep reactivity, a trait-like degree to which stress exposure disrupts sleep, are both constructs that tap into similar elements of perceived distress and impairment. This study aimed to examine associations between perceived distress and impairment from insomnia, pain catastrophizing, pain interference, and sleep reactivity. Methods Participants from an online database were asked to complete the Insomnia Severity Index (ISI), Pain Catastrophizing Scale, McGill Pain Questionnaire, PROMIS Pain Interference Questionnaire, and the Ford Insomnia Response to Stress Test. Participants (n =398) were predominantly female (79%) and White (74%). The ISI was analyzed as two separate factors (i.e., F1 or the insomnia symptoms factor = items 1-3 and F2 or the insomnia-related impairment factor = items 4-7). Results Multiple adjusted regressions revealed that perceived insomnia distress and impairment (i.e., F2) was significantly related to pain catastrophizing (t = 2.18, p = .03) and pain interference (t = 3.55, p <.001), independent of insomnia and pain severity. Sleep reactivity was also significantly related to pain catastrophizing (t = 3.71, p > .001), even after adjusting for insomnia and pain severity. Conclusion Results suggest that the perceived distress and impairment resulting from insomnia, pain, and stressful events may represent a transdiagnostic vulnerability. Future research is needed to determine whether this pattern of distress and impairment extends to objective measures, such as actigraphy. This pattern of perceived distress and impairment could represent a viable intervention target. Support (if any)
Abstract Introduction Cognitive Behavioral Therapy for Insomnia (CBT-I) is a highly efficacious behavioral intervention for insomnia. However, no one has quantified to what extent United States ...citizens are familiar with or have used CBT-I (compared to other treatments like medication). This descriptive analyses study assessed the proportion of Americans that were familiar with and have used forms of sleep intervention, including CBT-I. Methods 3,082 participants across the United States were surveyed through Cloudresearch Connect. The mean age was 39.6 (Range = 18-85). The sample comprised of 48.7% women and 71.3% identified as White. Participants were asked (on a 7 point Likert scale) questions about sleep health. Participants were asked about their familiarity with insomnia treatments including: prescription and over-the-counter (OTC) medications, Melatonin, CBTI, Sleep Hygiene, Sleep Restriction Therapy (SRT), Stimulus Control Therapy (SCT), Relaxation or Mindfulness Meditation Therapy, and Light Therapy. Participants were asked if they had used any treatments prior to or within the past 12 months. Participants also completed the Insomnia Severity Index (ISI). Results Participants rated the importance of sleep on their physical (M = 6.2; SD = 0.99) and mental (M = 6.4; SD = 0.96) health. 52.7% of the participants had at least subthreshold insomnia (ISI score < 8). 17.7% had clinically elevated insomnia (ISI score > 15). As for familiarity with various sleep treatments, 65.5% recognized prescription medications (e.g., Ambien), 69.3% recognized OTC medications (e.g., antihistamines), 80.5% recognized melatonin, 15.1% recognized CBT-I, 26% recognized sleep hygiene, 4.4% recognized SRT, 5% recognized SCT, 47% recognized Relaxation or Mindfulness Meditation Therapy, and 26.4% recognized Light Therapy. Among participants with at least subthreshold levels of insomnia, only 3.6% used CBT-I in the past 12 months, and 5% had used it at least once. In the past 12 months, 49.2% had used OTC medication and 13.8% had used prescription medications. Conclusion The data shows that CBT-I remains under-utilized. The majority of participants only knew of medication (prescription and OTC) treatments for insomnia. Efforts to identify and address the barriers to increasing awareness and availability of CBT-I are important and could help struggling insomniacs compared to other methods previously attempted. Support (if any)
During eukaryotic transcription, RNA polymerase II undergoes dynamic post-translational modifications on the C-terminal domain (CTD) of the largest subunit, generating an information-rich PTM ...landscape that transcriptional regulators bind. The phosphorylation of Ser5 and Ser2 of CTD heptad occurs spatiotemporally with the transcriptional stages, recruiting different transcriptional regulators to Pol II. To delineate the protein interactomes at different transcriptional stages, we reconstructed phosphorylation patterns of the CTD at Ser5 and Ser2 in vitro. Our results showed that distinct protein interactomes are recruited to RNA polymerase II at different stages of transcription by the phosphorylation of Ser2 and Ser5 of the CTD heptads. In particular, we characterized calcium homeostasis endoplasmic reticulum protein (CHERP) as a regulator bound by phospho-Ser2 heptad. Pol II association with CHERP recruits an accessory splicing complex whose loss results in broad changes in alternative splicing events. Our results shed light on the PTM-coded recruitment process that coordinates transcription.
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•We used in vitro reconstruction to generate the pS2/pS5 species of the CTD of Pol II•Pol II phosphorylated at S5/S2 recruits different regulators with ongoing transcription•Novel regulators specifically recruited by certain phosphoryl CTD are identified•CHERP specifically interacts with pSer2 Pol II through a CID module
Biological sciences; Biochemistry; Molecular biology; Molecular mechanism of gene regulation
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