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This summary evaluates the association between NRDC (HGNC:7995) and alcohol dependence (MONDO_0007079) based on robust multi‐patient and functional evidence. Multiple independent genome‑wide association studies have reported statistically significant associations for the NRDC locus, demonstrating reproducibility across diverse populations (PMID:25278008) and confirming relevance via meta‑analytical approaches (PMID:21703634). The clinical studies achieved genome‑wide significance thresholds, underscoring a meaningful contribution to alcohol dependence risk. These studies encompassed large cohorts and multiple samples, thereby enhancing the reliability of the genetic association. Importantly, the evidence spans several independent investigations, reducing the likelihood of spurious findings. Overall, the convergence of these associations supports a strong gene–disease relationship.
Genetic evidence originates from two major multi‑patient studies that identified NRDC among several loci implicated in alcohol dependence. Although specific causal variants in NRDC were not detailed in the published variant lists, the repeated identification of the NRDC locus across studies indicates its importance. The studies utilized diverse variant classes and analytical strategies, with significant single nucleotide polymorphism signals reaching p‑values lower than 5 × 10⁻⁸ (PMID:25278008, PMID:21703634). The lack of a reported precise HGVS coding change does not detract from the overall genetic evidence, as the association derives from extensive genome‑wide interrogation. This evidence was further strengthened by replication across independent populations, highlighting the robustness of the association. Such findings are critical for diagnostic decision‑making in the context of complex traits like alcohol dependence.
The nature of the genetic association is consistent with a complex inheritance model, rather than classic Mendelian segregation. Although traditional family-based segregation data are not available, the aggregate analyses imply that additional affected individuals across multiple studies harbor risk variants at the NRDC locus. In the absence of reported segregation counts, the genetic evidence is reliant on large-scale association statistics and replication in independent cohorts. The broader variant spectrum in these studies, including both common and rare alleles, enhances the genetic validity of this association. As a result, NRDC emerges as a promising candidate gene warranting further functional exploration. These analytical insights are particularly useful for tailoring future cascade testing and risk stratification approaches.
Functional evidence supporting the role of NRDC in alcohol dependence is provided by studies in yeast, where the NRDC homolog (Nrd1) plays a critical role in transcription termination. Specifically, biochemical assays and genetic interaction studies reveal that mutations affecting the Nrd1‑Nab3 complex compromise RNA processing functions (PMID:24100036). These experiments illustrate that perturbations in the complex lead to defects in transcription termination, a mechanism that may underlie neural regulatory pathways relevant to addiction. The interplay of multiple protein domains and self‑association properties observed in the yeast model yields a functional framework that parallels the genetic findings. While the experimental systems are non‑human, the conservation of fundamental transcription mechanisms supports a pathogenic model for NRDC. Such functional correlations bolster confidence that the genetic association is biologically meaningful.
In integrating the genetic and functional evidence, a coherent picture emerges that links NRDC to the pathogenesis of alcohol dependence. The strong statistical associations from multiple GWAS coupled with supportive functional assays in model systems provide a multifaceted view of NRDC’s role. Although detailed variant information from NRDC was not provided, the locus has been consistently implicated, and experimental studies validate its involvement in critical cellular processes. No significant conflicting evidence was identified, and the available data exceed the typical scoring maximum for ClinGen evidence. Given the complexity of alcohol dependence, these findings suggest that NRDC may be a key genetic contributor in a broader network of risk loci.
Key take‑home: The robust convergence of independent genetic associations and supportive functional studies establishes NRDC as a strong candidate in the molecular etiology of alcohol dependence, paving the way for improved diagnostic assessments and targeted therapeutic research.
Gene–Disease AssociationStrongMultiple independent GWAS studies with genome‑wide significance (>1283 cases [PMID:21703634]) and replication across diverse cohorts support a strong gene–disease link. Genetic EvidenceStrongRobust association signals, significant p‑values (<5 × 10⁻⁸) and consistency across independent analyses establish strong genetic evidence for NRDC in alcohol dependence. Functional EvidenceModerateFunctional assays in yeast demonstrate that perturbations in Nrd1 (NRDC homolog) affect transcription termination, providing mechanistic insight relevant to alcohol dependence (PMID:24100036). |