Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.Genetics of disease, diagnosis and treatmen

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders (vol 108, pg 1692, 2021)

Neurolog

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

How Can We Better Help Cancer Patients Quit Smoking? The London Regional Cancer Program Experience with Smoking Cessation

Background: Because continued cigarette smoking after a cancer diagnosis is associated with detrimental outcomes, supporting cancer patients with smoking cessation is imperative. We evaluated the effect of the Smoking Cessation Program at the London Regional Cancer Program (lrcp) over a 2-year period. Methods: The Smoking Cessation Program at the lrcp began in March 2014. New patients are screened for tobacco use. Tobacco users are counselled about the benefits of cessation and are offered referral to the program. If a patient accepts, a smoking cessation champion offers additional counselling. Follow-up is provided by interactive voice response (ivr) telephone system. Accrual data were collected monthly from January 2015 to December 2016 and were evaluated. Results: During 2015–2016, 10,341 patients were screened for tobacco use, and 18% identified themselves as current or recent tobacco users. In 2015, 84% of tobacco users were offered referral, but only 13% accepted, and 3% enrolled in ivr follow-up. At the lrcp in 2016, 77% of tobacco users were offered referral to the program, but only 9% of smokers accepted, and only 2% enrolled in ivr follow-up. Conclusions: The Smoking Cessation Program at the lrcp has had modest success, because multiple factors influence a patient\u27s success with cessation. Limitations of the program include challenges in referral and counselling, limited access to nicotine replacement therapy (nrt), and minimal follow-up. To mitigate some of those challenges, a pilot project was launched in January 2017 in which patients receive free nrt and referral to the local health unit

Monitoring anthropogenic particles in the environment: Recent developments and remaining challenges at the forefront of analytical methods

Anthropogenic particles at the microscale and nanoscale are posing risks to human health and the ecosystem. Engineered nanomaterials, microplastics and nanoplastics, soot, road and tire wear are a few prominent examples of particles that are either intentionally manufactured or incidentally produced and released into the environment. Analytical developments in the past few decades have made it possible to study particles in the microscale and nanoscale; however, there is still no universal protocol of analysis and caveats exist in the use of the most prominent techniques. The task is challenging because of the large variety of particle properties and the complexity of environmental media. This review discusses a selected group of techniques most likely to play a key role in future monitoring activities and their recent developments and inherent shortcomings. © 2021 The Author

Evaluation of the effectiveness of air pollution control measures in Hong Kong

From 2005 to 2013, volatile organic compounds (VOCs) and other trace gases were continuously measured at a suburban site in Hong Kong. The measurement data showed that the concentrations of most air pollutants decreased during these years. However, ozone (O3) and total non-methane hydrocarbon levels increased with the rate of 0.23 ± 0.03 and 0.34 ± 0.02 ppbv/year, respectively, pointing to the increasing severity of photochemical pollution in Hong Kong. The Hong Kong government has ongoing programs to improve air quality in Hong Kong, including a solvent program implemented during 2007–2011, and a diesel commercial vehicle (DCV) program since 2007. From before to after the solvent program, the sum of toluene, ethylbenzene and xylene isomers decreased continuously with an average rate of −99.1 ± 6.9 pptv/year, whereas the sum of ethene and propene increased by 48.2 ± 2.0 pptv/year from before to during the DCV program. Despite this, source apportionment results showed that VOCs emitted from diesel exhaust decreased at a rate of −304.5 ± 17.7 pptv/year, while solvent related VOCs decreased at a rate of −204.7 ± 39.7 pptv/year. The gasoline and liquefied petroleum gas vehicle emissions elevated by 1086 ± 34 pptv/year, and were responsible for the increases of ethene and propene. Overall, the simulated O3 rate of increase was lowered from 0.39 ± 0.03 to 0.16 ± 0.05 ppbv/year by the solvent and DCV programs, because O3 produced by solvent usage and diesel exhaust related VOCs decreased (p < 0.05) by 0.16 ± 0.01 and 0.05 ± 0.01 ppbv/year between 2005 and 2013, respectively. However, enhanced VOC emissions from gasoline and LPG vehicles accounted for most of the O3 increment (0.09 ± 0.01 out of 0.16 ± 0.05 ppbv/year) in these years. To maintain a zero O3 increment in 2020 relative to 2010, the lowest reduction ratio of VOCs/NOx was ∼1.5 under the NOx reduction of 20–30% which was based on the emission reduction plan for Pearl River Delta region in 2020