New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
Authors: Alemany, Silvia; Ribases, Marta; Vilor-Tejedor, Natalia; Bustamante, Mariona; Sanchez-Mora, Cristina; Bosch, Rosa; Richarte, Vanesa; Cormand, Bru; Casas, Miguel; Ramos-Quiroga, Josep A.; Sunyer, Jordi
Abstract
Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P<5E-08), 27 loci showed suggestive evidence of association with the CPT outcomes (P
A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence
AMERICAN JOURNAL OF HUMAN GENETICS
Authors: Lou, Xiang-Yang; Chen, Guo-Bo; Yan, Lei; Ma, Jennie Z.; Zhu, Jun; Elston, Robert C.; Li, Ming D.
Abstract
The determination of gene-by-gene and gene-by-environment interactions has long been one of the greatest challenges in genetics. The traditional methods are typically inadequate because of the problem referred to as the "curse of dimensionality." Recent combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, the combinatorial partitioning method, and the restricted partition method, have a straightforward correspondence to the concept of the phenotypic landscape that unifies biological, statistical genetics, and evolutionary theories. However, the existing approaches have several limitations, such as not allowing for covariates, that restrict their practical use. In this study, we report a generalized MDR (GMDR) method that permits adjustment for discrete and quantitative covariates and is applicable to both dichotomous and continuous phenotypes in various population-based study designs. Computer simulations indicated that the GMDR method has superior performance in its ability to identify epistatic loci, compared with current methods in the literature. We applied our proposed method to a genetics study of four genes that were reported to be associated with nicotine dependence and found significant joint action between CHRNB4 and NTRK2. Moreover, our example illustrates that the newly proposed GMDR approach can increase prediction ability, suggesting that its use is justified in practice. In summary, GMDR serves the purpose of identifying contributors to population variation better than do the other existing methods.