NKAIN1-SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent.
- Authors
- Zuo, Lingjun; Wang, Kesheng; Zhang, Xiang-Yang; Krystal, John H; Li, Chiang-Shan R; Zhang, Fengyu; Zhang, Heping; Luo, Xingguang
- Year
- 2013
- Journal
- Drug and alcohol dependence
- PMID
- 23455491
- DOI
- 10.1016/j.drugalcdep.2013.02.006
- PMCID
- PMC3628730
OBJECTIVE: We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs). METHODS: A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis. RESULTS: A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10(-7)≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4×10(-7)) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence. CONCLUSION: NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.
Regional association and cis-eQTL plots around NKAIN1-SERINC2 region [Left Y-axis corresponds to -log(p) value; right Y-axis corresponds to recombination rates; quantitative color gradient corresponds to r2; red squares represent peak SNPs. (A) regional association plot in European-American discovery samples for a 10Mb region around the peak association SNP (rs4949399) in NKAIN1-SERINC2; (B–C) regional association plots in European-American discovery samples and Australians for a 1Mb region around the peak association SNP (rs4949399) in NKAIN1-SERINC2; (D–H) regional eQTL plots in HapMap populations and European samples for a 1Mb region around rs4949399; only the effects on local gene expression are illustrated (the effects on flanking gene expression are presented in Table S4); (I) LD map for NKAIN1-SERINC2 region; red bars on the top represent the peak SNPs in this region in each population. All markers in Figure 1 are non-imputed.]
LLM interpretation
This figure consists of multiple regional association and eQTL Manhattan plots (A–H) and a linkage disequilibrium (LD) heat map (I) centered on the *NKAIN1-SERINC2* region. Panels A–C show genetic associations in European-American and Australian populations, while panels D–H display eQTL effects across various HapMap and European samples, with the y-axis representing $-\log(p)$ values and the x-axis representing genomic position. The LD map (I) uses a red color gradient to show correlation ($r^2$) across a 246kb region, with red bars indicating peak SNPs for each population.
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| NKAIN1 expression relates to the immune evasion and prognosis of gastric cancer. | Zhou L et al. | — | 2025 | → |
| Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people. | Koyanagi YN et al. | — | 2024 | → |
| Phenome-wide association studies between <i>SERINC2</i> and neuropsychiatric disorders. | Liu P et al. | — | 2024 | → |
| Common and distinguishing genetic factors for substance use behavior and disorder: an integrated analysis of genomic and transcriptomic studies from both human and animal studies. | Chang XW et al. | — | 2022 | → |
| Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder. | Czamara D et al. | — | 2022 | → |
| SERINC2 increases the risk of bipolar disorder in the Chinese population. | Yang D et al. | — | 2021 | → |
| Discovering weaker genetic associations guided by known associations. | Wang H et al. | — | 2020 | → |
| Genetic determinants of beverage consumption: Implications for nutrition and health. | Cornelis MC | — | 2019 | → |
| Shared additive genetic variation for alcohol dependence among subjects of African and European ancestry. | Brick LA et al. | — | 2019 | → |
| Human Genetics of Addiction: New Insights and Future Directions. | Hancock DB et al. | — | 2018 | → |
| Peripheral Acid Sphingomyelinase Activity Is Associated with Biomarkers and Phenotypes of Alcohol Use and Dependence in Patients and Healthy Controls. | Mühle C et al. | — | 2018 | → |
| Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder. | Hnoonual A et al. | — | 2017 | → |
| Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence. | Clark SL et al. | — | 2017 | → |
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| Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent. | Zuo L et al. | — | 2013 | → |