ORCID Profile
0000-0003-2888-9051
Current Organisations
School of Medicine, Indiana University
,
Indiana University-Purdue University Indianapolis
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Publisher: Elsevier BV
Date: 12-2020
Publisher: Cold Spring Harbor Laboratory
Date: 16-09-2021
DOI: 10.1101/2021.09.13.21263503
Abstract: Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant in OPRM1 , has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective s le size of 88,114 in iduals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r g 0.9). We observed the strongest evidence to date for OPRM1 : lead SNP rs9478500 ( p =2.56×10 −9 ). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN . Variants within these loci appear to be pleiotropic for addiction and related traits.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2020
Publisher: Wiley
Date: 16-02-2020
DOI: 10.1111/ADB.12880
Publisher: Elsevier BV
Date: 06-2019
Publisher: Springer Science and Business Media LLC
Date: 07-01-2019
DOI: 10.1038/S41380-018-0313-0
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P 5 × 10 −8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits ( P 5 × 10 −8 ) in the discovery s les. Ten novel SNVs, including rs12616219 near TMEM182 , were followed-up and five of them (rs462779 in REV3L , rs12780116 in CNNM2 , rs1190736 in GPR101 , rs11539157 in PJA1 , and rs12616219 near TMEM182 ) replicated at a Bonferroni significance threshold ( P 4.5 × 10 −3 ) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2 . Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
Location: United States of America
Location: United States of America
No related grants have been discovered for Leah Wetherill.