Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.
Drug Alcohol Depend
; 188: 94-101, 2018 07 01.
Article
en En
| MEDLINE
| ID: mdl-29758381
ABSTRACT
BACKGROUND:
Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.METHODS:
We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (Nâ¯=â¯25,508) and "tobacco use disorder" (Nâ¯=â¯27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.RESULTS:
The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (pâ¯=â¯2.39â¯×â¯10-7) and rs8034191 (pâ¯=â¯6.31â¯×â¯10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.DISCUSSION:
Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
2_ODS3
/
8_ODS3_consumo_sustancias_psicoactivas
Problema de salud:
2_sustancias_psicoativas
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8_alcohol
Asunto principal:
Variación Genética
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Consumo de Bebidas Alcohólicas
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Exones
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Predisposición Genética a la Enfermedad
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Uso de Tabaco
Tipo de estudio:
Diagnostic_studies
/
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Drug Alcohol Depend
Año:
2018
Tipo del documento:
Article