Dataset Information

Heritability, SNP- and Gene-Based Analyses of Cannabis Use Initiation and Age at Onset.

ABSTRACT: Prior searches for genetic variants (GVs) implicated in initiation of cannabis use have been limited to common single nucleotide polymorphisms (SNPs) typed in HapMap samples. Denser SNPs are now available with the completion of the 1000 Genomes and the Genome of the Netherlands projects. More densely distributed SNPs are expected to track the causal variants better. Therefore we extend the search for variants implicated in early stages of cannabis use to previously untagged common and low-frequency variants. We run heritability, SNP and gene-based analyses of initiation and age at onset. This is the first genome-wide study of age at onset to date. Using GCTA and a sample of distantly related individuals from the Netherlands Twin Register, we estimated that the currently measured (and tagged) SNPs collectively explain 25 % of the variance in initiation (SE = 0.088; P = 0.0016). Chromosomes 4 and 18, previously linked with cannabis use and other addiction phenotypes, account for the largest amount of variance in initiation (6.8 %, SE = 0.025, P = 0.002 and 3.6 %, SE = 0.01, P = 0.012, respectively). No individual SNP- or gene-based test reached genomewide significance in the initiation or age at onset analyses. Our study detected association signal in the currently measured SNPs. A comparison with prior SNP-heritability estimates suggests that at least part of the signal is likely coming from previously untyped common and low frequency variants. Our results do not rule out the contribution of rare variants of larger effect-a plausible source of the difference between the twin-based heritability estimate and that from GCTA. The causal variants are likely of very small effect (i.e., <1 % explained variance) and are uniformly distributed over the genome in proportion to chromosomes' length. Similar to other complex traits and diseases, detecting such small effects is to be expected in sufficiently large samples.

SUBMITTER: Minica CC

PROVIDER: S-EPMC4561059 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Heritability, SNP- and Gene-Based Analyses of Cannabis Use Initiation and Age at Onset.

Minică Camelia C CC Dolan Conor V CV Hottenga Jouke-Jan JJ Pool René R Fedko Iryna O IO Mbarek Hamdi H Huppertz Charlotte C Bartels Meike M Boomsma Dorret I DI Vink Jacqueline M JM

Behavior genetics 20150519 5

Prior searches for genetic variants (GVs) implicated in initiation of cannabis use have been limited to common single nucleotide polymorphisms (SNPs) typed in HapMap samples. Denser SNPs are now available with the completion of the 1000 Genomes and the Genome of the Netherlands projects. More densely distributed SNPs are expected to track the causal variants better. Therefore we extend the search for variants implicated in early stages of cannabis use to previously untagged common and low-freque ...[more]

PMID: 25987507

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Project description:Abstract Background Cannabis use, particularly regular use in adolescence, is associated with an increased risk of developing psychosis earlier. An earlier age of onset negates the protective effects of more mature psychosocial and individual variables, thus the potential for worse outcomes. Genetic variations in this relationship are important to understand as this will allow not only a better understanding of the biological interaction of cannabis and psychosis, but would inform future genetic approaches to risk identification as well. We uniquely examined the mediation of this association (gene x cannabis associations in age of onset of psychosis (AoP)) in 3 genetic variants which, while each have been examined separately, not in combination in the same population. We examined: 1) COMT Val158Met (rs4680) 2) BDNF Val66Met (rs6265) and 3) the AKT1 variant rs2494732. Methods 168 subjects with a diagnosis of psychosis were recruited from 2 sites in Canada, Edmonton Alberta and Halifax Nova Scotia. Cannabis use data (age at first and regular use) were collected using an electronic self-report survey (to address potential minimization of use to a researcher) and saliva samples were used for genotyping. Kaplan-Meier and Cox regression analyses were used to study the gene – cannabis effects. Results In those who had used cannabis, first use of cannabis prior to 20 years of age was associated with earlier AoP (p = .005). In those who used cannabis before age 20, rs4680 had a trend level association with AoP (log rank test: p=0.0617). A trend effect for an rs6265 x gender interaction (HR = 2.08, p = 0.067) on AoP, controlling for regular cannabis use was also observed. No association was observed between rs2494732 and rs6265 - rs2494732 interaction, and AoP. Discussion The trends in our associations are in keeping with previous literature, however our gender analyses underscores the importance of examining sex and gender as we further move towards risk identification for the cannabis and psychosis interaction. Our results also suggest that not all genetic variants associated with psychosis are involved with the association between cannabis and AoP. While our results offer support for future research in this area, larger sample sizes are required to test the gene-cannabis-AoP relationship.

Dataset Information

Heritability, SNP- and Gene-Based Analyses of Cannabis Use Initiation and Age at Onset.

Publications

Heritability, SNP- and Gene-Based Analyses of Cannabis Use Initiation and Age at Onset.

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