Dataset Information

Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence.

ABSTRACT: The gray matter volume (GMV) of the putamen has been reported to be regulated by kinectin 1 gene (KTN1). As a hub of the dopaminergic circuit, the putamen is widely implicated in the etiological processes of substance use disorders (SUD). Here, we aimed to identify robust and reliable associations between KTN1 SNPs and SUD across multiple samples. We examined the associations between SUD and KTN1 SNPs in four independent population-based or family-based samples (n = 10,209). The potential regulatory effects of the risk alleles on the putamen GMVs, the effects of alcohol, nicotine, marijuana and cocaine on KTN1 mRNA expression, and the relationship between KTN1 mRNA expression and SUD were explored. We found that a total of 23 SNPs were associated with SUD across at least two independent samples (1.4 × 10^-4 ? p ? 0.049), including one SNP (rs12895072) across three samples (8.8 × 10^-3 ? p ? 0.049). Four other SNPs were significantly or suggestively associated with SUD only in European-Australians (4.8 × 10^-4 ? p ? 0.058). All of the SUD-risk alleles of these 27 SNPs increased (? > 0) the putamen GMVs and represented major alleles (f > 0.5) in Europeans. Twenty-two SNPs were potentially biologically functional. Alcohol, nicotine and cocaine significantly affected the KTN1 mRNA expression, and the KTN1 mRNA was differentially expressed between nicotine or cocaine dependent and control subjects. We concluded that there was a replicable and robust relationship among the KTN1 variants, KTN1 mRNA expression, putamen GMVs, molecular effects of substances, and SUD, suggesting that some risk KTN1 alleles might increase kinectin 1 expression in the putamen, altering putamen structures and functions, and leading to SUD.

SUBMITTER: Luo X

PROVIDER: S-EPMC7641293 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence.

Luo Xingguang X Guo Xiaoyun X Luo Xingqun X Tan Yunlong Y Zhang Ping P Yang Kebing K Xie Ting T Shi Jing J Zhang Yong Y Xu Jianying J Zuo Lingjun L Li Chiang-Shan R CR

Addiction biology 20200301 2

The gray matter volume (GMV) of the putamen has been reported to be regulated by kinectin 1 gene (KTN1). As a hub of the dopaminergic circuit, the putamen is widely implicated in the etiological processes of substance use disorders (SUD). Here, we aimed to identify robust and reliable associations between KTN1 SNPs and SUD across multiple samples. We examined the associations between SUD and KTN1 SNPs in four independent population-based or family-based samples (n = 10,209). The potential regula ...[more]

PMID: 32115811

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Project description:Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10-5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10-12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10-4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10-3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10-3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10-19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10-19 ≤ p ≤ 1.0 × 10-4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.

Project description:BACKGROUND:Alcohol and nicotine codependence can be considered as a more severe subtype of alcohol dependence. A portion of its risk may be attributable to genetic factors. METHODS:We searched for significant risk genomic regions specific for this disorder using a genome-wide association study. A total of 8,847 subjects underwent gene-disease association analysis, including (i) a discovery cohort of 818 European American cases with alcohol and nicotine codependence and 1,396 European American controls, (ii) a replication cohort of 5,704 Australian family subjects with 907 affected offspring, and (iii) a replication cohort of 449 African American cases and 480 African American controls. Additionally, a total of 38,714 subjects of European or African descent in 18 independent cohorts with 10 other nonalcoholism neuropsychiatric disorders were analyzed as contrast. Furthermore, 90 unrelated HapMap CEU individuals, 93 European brain tissue samples, and 80 European peripheral blood mononuclear cell samples underwent cis-acting expression quantitative locus (cis-eQTL) analysis. RESULTS:We identified a significant risk region for alcohol and nicotine codependence between IPO11 and HTR1A on chromosome 5q that was reported to be suggestively associated with alcohol dependence previously. In the European American discovery cohort, 381 single nucleotide polymorphisms (SNPs) in this region were nominally associated with alcohol and nicotine codependence (p < 0.05); 57 associations of them survived region- and cohort-wide correction (? = 3.6 × 10(-6) ); and the top SNP (rs7445832) was significantly associated with alcohol and nicotine codependence at the genome-wide significance level (p = 6.2 × 10(-9) ). Furthermore, associations for 34 and 11 SNPs were replicated in the Australian and African American replication cohorts, respectively. Among these replicable associations, 4 reached genome-wide significance level in the meta-analysis of European Americans and European Australians: rs7445832 (p = 9.6 × 10(-10) ), rs13361996 (p = 8.2 × 10(-9) ), rs62380518 (p = 2.3 × 10(-8) ), and rs7714850 (p = 3.4 × 10(-8) ). Cis-eQTL analysis showed that many risk SNPs in this region had nominally significant cis-acting regulatory effects on HTR1A or IPO11 mRNA expression. Finally, no markers were significantly associated with any other neuropsychiatric disorder examined. CONCLUSIONS:We speculate that this IPO11-HTR1A region might harbor a causal variant for alcohol and nicotine codependence.

Project description:Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10-5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10-22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Project description:Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p < .05) risk SNPs were classified into independent haplotype blocks. All SNPs, including imputed SNPs within these blocks, and haplotypes across each block, were explored for replication of associations in both samples. The potential biological functions of all risk SNPs were predicted using a series of bioinformatics analyses, their regulatory effects on the putamen volumes were tested, and the KTN1 mRNA expression was examined in three independent human putamen tissue samples. We found that fifteen SNPs were nominally associated with ADHD (p < .05) in the first sample, and three of them remained significant even after correction for multiple testing (1.3 × 10-10 ≤ p ≤ 1.2 × 10-4 ; α = 2.5 × 10-3 ). These 15 risk SNPs were located in five haplotype blocks, and 13 SNPs within four of these blocks were associated with ADHD in the second sample. Six haplotypes within these blocks were also significantly (1.2 × 10-7 ≤ p ≤ .009) associated with ADHD in these samples. These risk variants were located in disease-related transposons and/or transcription-related functional regions. Major alleles of these risk variants significantly increased putamen volumes. Finally, KTN1 mRNA was significantly expressed in putamen across three independent cohorts. We concluded that the KTN1 variants were significantly associated with ADHD. KTN1 may play a functional role in the development of ADHD.

Dataset Information

Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence.

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Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence.

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