Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits

Al-Soufi, Laila; Costas, Javier

doi:10.1016/j.drugalcdep.2021.108517

Cited by 5 publications

(7 citation statements)

References 32 publications

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“…One locus that deserves special attention is CHRNA2 . At this gene, we confirmed the previously found common association signal between SCZ, smoking, and CUD (Al-Soufi & Costas, 2021). We also found colocalization at this locus with the number of sexual partners, but in the opposite direction to that expected if externalizing behavior was involved.…”

Section: Discussionsupporting

confidence: 90%

“…CHRNA2 gene was also associated with cannabis use disorder (CUD) (Demontis et al, 2019). Although our previous work revealed that the main association signals for SCZ and smoking at the CHRNA5-CHRNA3-CHRNB4 cluster were independent, it demonstrated that the signal at the CHRNA2 gene colocalized (Al-Soufi & Costas, 2021). This may be due to a causal effect of substance use on SCZ (i.e.…”

Section: Introductionmentioning

confidence: 88%

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Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits

Al-Soufi

Costas

2023

Psychol. Med.

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Background Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking. Methods Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original v. conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings. Results Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as CHRNA2, CUL3, and PCDH7. Conclusions Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 88%

Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits

Al-Soufi

Costas

2023

Psychol. Med.

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“…The searching regions of colocalization are not consistent across studies. One study defined the regions within 500 kb of the lead SNPs, 63 another study searched for significant SNPs at ±200 kb of the transcribed region of interest, 64 and another study defined test regions from MR-independent SNPs within 200 kb distance to define 118 unique regions. 65 In this study, we searched for the lead SNP within a region of ±1 MB and repeated the colocalization analysis within ±3 MB using all the GWAS data.…”

Section: Methodsmentioning

confidence: 99%

A Mendelian randomization-based exploration of red blood cell distribution width and mean corpuscular volume with risk of hemorrhagic strokes

Liu¹,

Chou²,

Lau³

et al. 2022

Human Genetics and Genomics Advances

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“…Association of SNPs at CHRNA5–CHRNA3–CHRNB4 cluster was analysed by logistic regression using an additive genetic model. Taking into account that the strongest signals in the GWAS of schizophrenia and smoking traits did not co‐localized, 38 two SNPs were considered: the functional SNP D398N at CHRNA5 (dbSNP ID: rs16969968), 39 associated with several smoking traits 11,12 and the most significantly associated SNP with schizophrenia at this cluster, rs8042374 9 . Both SNPs are in partial LD ( r 2 = 0.18 in European samples of the 1000 Genomes Phase 3 according to LDlink 40 ).…”

Section: Methodsmentioning

confidence: 99%

“…37 Association of SNPs at CHRNA5-CHRNA3-CHRNB4 cluster was analysed by logistic regression using an additive genetic model. Taking into account that the strongest signals in the GWAS of schizophrenia and smoking traits did not co-localized, 38 two SNPs were considered:…”

Section: Statistical Analysesmentioning

confidence: 99%

A polygenic approach to the association between smoking and schizophrenia

et al. 2021

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Smoking prevalence in schizophrenia is considerably larger than in general population, playing an important role in early mortality. We compared the polygenic contribution to smoking in schizophrenic patients and controls to assess if genetic factors may explain the different prevalence. Polygenic risk scores (PRSs) for smoking initiation and four genetically correlated traits were calculated in 1108 schizophrenic patients (64.4% smokers) and 1584 controls (31.1% smokers). PRSs for smoking initiation, educational attainment, body mass index and age at first birth were associated with smoking in patients and controls, explaining a similar percentage of variance in both groups. Attention-deficit hyperactivity disorder (ADHD) PRS was associated with smoking only in schizophrenia. This association remained significant after adjustment by psychiatric cross-disorder PRS. A PRS combining all the traits was more explanative than smoking initiation PRS alone, indicating that genetic susceptibility to the other traits plays an additional role in smoking behaviour. Smoking initiation PRS was also associated with schizophrenia in the whole sample, but the significance was lost after adjustment for smoking status. This same pattern was observed in the analysis of specific SNPs at the CHRNA5-CHRNA3-CHRNB4 cluster associated with both

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Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits

Cited by 5 publications

References 32 publications

Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits

Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits

A Mendelian randomization-based exploration of red blood cell distribution width and mean corpuscular volume with risk of hemorrhagic strokes

A polygenic approach to the association between smoking and schizophrenia

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