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. 2022 Nov 22;10(12):3007.
doi: 10.3390/biomedicines10123007.

A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures

Anastasia Levchenko  1 , Sergey Malov  1   2   3 , Alexey Antonik  4 , Anastasia Protsvetkina  1 , Kseniya V Rybakova  5 , Alexander Kanapin  6 , Alexey N Yakovlev  7 , Anna Y Nenasteva  8 , Anton E Nikolishin  9 , Nikolay Cherkasov  10 , Natalia A Chuprova  9 , Anna S Blagonravova  11 , Angelica V Sergeeva  11 , Tatyana V Zhilyaeva  11 , Maria K Denisenko  11 , Raul R Gainetdinov  1   12 , Alexander O Kibitov  9   13 , Evgeny M Krupitsky  5   14
Affiliations

A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures

Anastasia Levchenko et al. Biomedicines. .

Abstract

At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33 × 10-8 calculated with the Yates-corrected χ2 test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWASs of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network, where BDNF is the most significant hub gene. This study indicates that several genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The study also reveals a central role of BDNF in the pathogenesis of AD.

Keywords: BDNF; alcohol dependence; comorbidity; gene network; genome-wide association study; sex differences.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Power of GWAS χ2 tests. The necessary number of cases was estimated with the following parameters: the control to case ratio = 5, α = 0.05 (Bonferroni-corrected p-value = 1 × 10−7, assuming there will 400,000 markers used in the analysis), disease prevalence = 0.1, minor allele frequency in the control group = 0.1, and the allelic odds ratio = 2.5.
Figure 2
Figure 2
Results of multidimensional scaling of this cohort and several large human populations. Indicated ancestries are: EUR—European, EAS—East Asian, AMR—American, AFR—African, SAS—South Asian. One outlier among cases (red cross) was excluded from the downstream analysis.
Figure 3
Figure 3
The population genetic structure of cases and controls estimated using the principal component analysis (PCA). The percentages of variance explained by the principal components (PC) are indicated for: (A) the first two PC; (B) the first four PC.
Figure 4
Figure 4
Interaction network of genes associated with AD and related phenotypes. The network is predicted by the String database. Genes colored in pink are associated with AD and related clinical measures in female patients; genes colored in blue are associated with AD and related clinical measures in male patients and the entire (predominantly male) cohort; genes colored in green were previously reported in the literature. The gene BDNF that was replicated in the present study and revealed in previous GWASs of alcohol phenotypes is colored in aquamarine. The thickness of edges indicates the strength of data support in terms of confidence scores: medium (0.4), high (0.7), highest (0.9). BDNF has the greatest number of connections (sixteen) with other nodes.
See this image and copyright information in PMC

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