Details

Autor(en) / Beteiligte

• Peng, Qian
• Wilhelmsen, Kirk C.
• Ehlers, Cindy L.

Titel

Pleiotropic loci for cannabis use disorder severity in multi-ancestry high-risk populations

Ist Teil von

• Molecular and cellular neuroscience, 2023-06, Vol.125, p.103852-103852, Article 103852

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Cannabis use disorder (CUD) is common and has in part a genetic basis. The risk factors underlying its development likely involve multiple genes that are polygenetic and interact with each other and the environment to ultimately lead to the disorder. Co-morbidity and genetic correlations have been identified between CUD and other disorders and traits in select populations primarily of European descent. If two or more traits, such as CUD and another disorder, are affected by the same genetic locus, they are said to be pleiotropic. The present study aimed to identify specific pleiotropic loci for the severity level of CUD in three high-risk population cohorts: American Indians (AI), Mexican Americans (MA), and European Americans (EA). Using a previously developed computational method based on a machine learning technique, we leveraged the entire GWAS catalog and identified 114, 119, and 165 potentially pleiotropic variants for CUD severity in AI, MA, and EA respectively. Ten pleiotropic loci were shared between the cohorts although the exact variants from each cohort differed. While majority of the pleiotropic genes were distinct in each cohort, they converged on numerous enriched biological pathways. The gene ontology terms associated with the pleiotropic genes were predominately related to synaptic functions and neurodevelopment. Notable pathways included Wnt/β-catenin signaling, lipoprotein assembly, response to UV radiation, and components of the complement system. The pleiotropic genes were the most significantly differentially expressed in frontal cortex and coronary artery, up-regulated in adipose tissue, and down-regulated in testis, prostate, and ovary. They were significantly up-regulated in most brain tissues but were down-regulated in the cerebellum and hypothalamus. Our study is the first to attempt a large-scale pleiotropy detection scan for CUD severity. Our findings suggest that the different population cohorts may have distinct genetic factors for CUD, however they share pleiotropic genes from underlying pathways related to Alzheimer's disease, neuroplasticity, immune response, and reproductive endocrine systems. •A large-scale pleiotropy scan for cannabis use disorder (CUD) in American Indians, Mexican Americans, and European Americans.•Identified ten pleiotropic loci for CUD severity shared between the populations.•Most pleiotropic genes were distinct in each population cohort, but they converged on several enriched pathways.•Enriched pathways were related to Alzheimer’s disease, neuroplasticity, immune response, & reproductive endocrine systems.•Notable pathways included Wnt/β-catenin signaling, lipoprotein assembly, response to UV radiation, & the complement system.•Pleiotropic genes were up-regulated in most brain & adipose tissues, down-regulated in testis, prostate, ovary, & HPA axis.