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A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts.

ABSTRACT: Studies of alcohol dependence (AD) have consistently found evidence of linkage on chromosome 4q21-q32. A genome-wide linkage scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample also provided its strongest evidence of linkage on chromosome 4q22-q32 using an index of AD severity based on the count of DSM-IV AD symptoms (ADSX; LOD = 4.59). We conducted a systematic, gene-centric association study using 518 LD-tagging single nucleotide polymorphisms (SNPs) in the 65 known and predicted genes within the 1-LOD interval surrounding the linkage peak. Case-only regression analysis with the quantitative variable of ADSX was performed in the 562 genetically independent cases; nominal support for association was demonstrated by 32 tagging SNPs in 14 genes. We did not observe study-wide significance, but gene-wise correction for multiple testing with the Nyholt procedure yielded empirical evidence of association with two genes, DKK2 (dickkopf homolog 2) (P = 0.007) and EGF (epidermal growth factor) (P = 0.025) in the IASPSAD sample. Three SNPs in DKK2 (rs427983; rs419558; rs399087) demonstrated empirical significance. Assessment of possible replication in 847 cases of European descent from a large independent sample, the Collaborative Study of the Genetics of Alcoholism, yielded replication for DKK2 but not EGF. We observed genotypic and phenotypic replication for DKK2 with the three SNPs yielding significant association with ADSX in the IASPSAD sample. Haplotype-specific expression measurements in post-mortem tissue samples suggested a functional role for DKK2. This evidence notwithstanding, replication is needed before confidence can be placed in these findings.

SUBMITTER: Kalsi G

PROVIDER: S-EPMC2876884 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts.

Kalsi Gursharan G Kuo Po-Hsiu PH Aliev Fazil F Alexander Jeffry J McMichael Omari O Patterson Diana G DG Walsh Dermot D Zhao Zhongming Z Schuckit Marc M Nurnberger John J Edenberg Howard H Kramer John J Hesselbrock Victor V Tischfield Jay A JA Vladimirov Vladimir V Prescott Carol A CA Dick Danielle M DM Kendler Kenneth S KS Riley Brien P BP

Human molecular genetics 20100323 12

Studies of alcohol dependence (AD) have consistently found evidence of linkage on chromosome 4q21-q32. A genome-wide linkage scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample also provided its strongest evidence of linkage on chromosome 4q22-q32 using an index of AD severity based on the count of DSM-IV AD symptoms (ADSX; LOD = 4.59). We conducted a systematic, gene-centric association study using 518 LD-tagging single nucleotide polymorphisms (SNPs) in the 65 know ...[more]

PMID: 20332099

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Project description:BackgroundAlthough alcohol use disorder can complicate depression management, there is no standard process for assessing AUD symptoms (i.e., AUD diagnostic criteria) in primary care for patients who screen positive for depression. This study characterizes the association between depressive symptoms and high-risk drinking reported by primary care patients on screening measures in routine care. Then, using data from a novel clinical program, this study characterizes the association between depressive symptoms and AUD symptoms reported by primary care patients with high-risk drinking via an Alcohol Symptom Checklist.MethodsIn this cross-sectional study, electronic health record data were obtained from patients who visited 33 Kaiser Permanente Washington primary care clinics between 03/2018 and 02/2020 and completed depression (PHQ-2) and alcohol consumption (AUDIT-C) screening measures as part of routine care (N = 369,943). Patients who reported high-risk drinking (AUDIT-C scores 7-12) also completed an Alcohol Symptom Checklist where they reported the presence or absence of 11 AUD criteria as defined by the DSM-5 (N = 8,184). Generalized linear models estimated and compared the prevalence of high-risk drinking (AUDIT-C scores 7-12) and probable AUD (2-11 AUD symptoms on Alcohol Symptom Checklists) for patients with and without positive depression screens.ResultsPatients who screened positive for depression had a 131% higher prevalence of high-risk drinking than those who screened negative (5.2% vs. 2.2%; p < 0.001). Among patients with high-risk drinking, positive depression screens were associated with a significantly higher prevalence of probable AUD (69.8% vs. 48.0%; p < 0.001), with large differences in the prevalence of probable AUD observed with increasing PHQ-2 scores (e.g., probable AUD prevalence of 37.6%, 55.3% and 65.2%, for PHQ-2 scores of 0, 1, and 2, respectively). Although the overall prevalence of high-risk drinking was higher for male patients, similar patterns of association between depression screens, high-risk drinking, and AUD symptoms were observed for male and female patients.ConclusionsPatients with positive depression screens are more likely to have high-risk drinking. Large percentages of patients with positive depression screens and high-risk drinking report symptoms consistent with AUD to healthcare providers when given the opportunity to do so using an Alcohol Symptom Checklist.

Dataset Information

A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts.

Publications

A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts.

Similar Datasets

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