Dataset Information

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

ABSTRACT: Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

SUBMITTER: Smith DR

PROVIDER: S-EPMC5690672 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

Smith Douglas R DR Stanley Christine M CM Foss Theodore T Boles Richard G RG McKernan Kevin K

PloS one 20171116 11

Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (esp ...[more]

PMID: 29145497

Similar Datasets

Project description:Studies investigating the association between gene variants and depression susceptibility found inconsistent data. The present study aimed to clarify whether CNR1rs1049353, CNR1 AAT triplet repeat, and CNR2rs2501432 polymorphisms confer higher risk for depressive disorder.Literature from PubMed, Medline, Embase, Scopus, Cochrance Library, and Wanfang databases was searched (up to August 20, 2018). Seven case-control studies with various comorbidities were eligible. We targeted CNR single-nucleotide polymorphisms (SNPs) that have been reported by 2 or more studies to be involved in the current meta-analysis, resulting in a final list of 3 SNPs: CNR1rs1049353, CNR1 AAT triplet repeat polymorphism, and CNR2rs2501432. Odds ratios (ORs) and 95% confidence intervals (CIs) for allele and homozygote comparisons, dominant and recessive models, and triplet repeat polymorphism ((AAT)n≥5, ≥5 vs (AAT)n<5, <5 or <5, ≥5) were assessed using a random effect model as measures of association. Heterogeneity among included studies was analyzed using sensitivity test. Publication bias was also explored by Egger and rank correlation test.overall, no significant association was found between depression and CNR1rs1049353 (G vs A: OR [95% CI] = 1.09 [0.61-1.95]; GG vs AA: 1.29 [0.73-2.26]; GG vs GA+AA: 1.10 [0.57-2.10]; GG+GA vs AA: 1.25 [0.72-2.18]; and AAT triplet repeat polymorphism ((AAT)n≥5, ≥5 vs (AAT)n<5, <5 or <5, ≥5): 1.92 [0.59-6.27]. In contrast, a significant association between CNR2rs2501432 and depression was detected, and the ORs and 95% CIs are as follows: allele contrast (OR = 1.39, 95% CI = [1.12-1.72], P = .003); homozygous (OR = 2.19, 95% CI = [1.34-3.59], P = .002); dominant (OR = 1.93,95% CI = [1.23-3.04], P = .005); and recessive (OR = 1.41, 95% CI = [1.04-1.92], P = .03).This meta-analysis revealed that CNR1rs1049353 or AAT triplet repeat polymorphism had no association with susceptibility to depression, while CNR2rs2501432 polymorphism was a remarkable mark for depression patients.

Project description:Inhibition of the endocannabinoid receptor CB1 improves insulin sensitivity, lowers glycemia, and slows atherosclerosis. We analyzed whether common variants in the gene encoding CB1, CNR1, are associated with insulin resistance, risk of type 2 diabetes (T2D) or coronary heart disease (CHD). We studied 2,411 participants of the Framingham Offspring Study (mean age 60 years, 52% women) for quantitative traits and CHD, and the Framingham SHARe database for T2D risk. We genotyped 19 single-nucleotide polymorphisms (SNPs) that tagged 85% (at r(2) = 0.8) of common (>5%) CNR1 SNPs. Fasting blood glucose and insulin at the 7th (1999-2001) exam were collected. We used age-, sex-, BMI-adjusted models to test additive associations of genotype with homeostasis model assessment of insulin resistance (HOMA(IR)) (linear mixed-effect models), T2D, or CHD. To account for multiple tests of SNPs, we generated empirical P values. The C allele at SNP rs806365 (frequency, 57.4%), ~4.1 kb 3' from CNR1, was associated with increased HOMA(IR) (n = 2,261, ? = 0.05 per C, empirical P = 0.01), risk of T2D (674 cases, odds ratio = 1.19 per C, nominal P = 0.01) and CHD (237 cases, hazard ratio = 1.23 per C, nominal P = 0.04). The association of rs806365 with HOMA(IR) was replicated in a meta-analysis of two independent cohorts (National Health and Nutrition Examination Survey III genetic cohort (NHANES-III) plus Partners Case-Control Diabetes Study; 2,540 white individuals, ? = 0.037, nominal P = 0.007), but not in the large Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Consortium (n = 29,248, nominal P = 0.74). The association of rs806365 was not replicated either with T2D in Diabetes Genetics Replication and Meta-analysis (DIAGRAM) (n = 10,128, nominal P = 0.31), or with CHD in PROCARDIS (n = 13,614, nominal P = 0.37). Although supported by initial results, we found no reproducible statistical association of common variation at CNR1 with insulin resistance, T2D, or CHD.

Dataset Information

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

Publications

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets