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Pharmacogenomic variants have larger effect sizes than genetic variants associated with other dichotomous complex traits.
Maranville JC, Cox NJ
(2016) Pharmacogenomics J 16: 388-92
MeSH Terms: Databases, Genetic, Drug-Related Side Effects and Adverse Reactions, Endophenotypes, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heredity, Humans, Pharmacogenomic Variants, Phenotype, Quantitative Trait, Heritable
Show Abstract · Added February 22, 2016
It has been suggested that pharmacogenomic phenotypes are influenced by genetic variants with larger effect sizes than other phenotypes, such as complex disease risk. This is presumed to reflect the fact that relevant environmental factors (drug exposure) are appropriately measured and taken into account. To test this hypothesis, we performed a systematic comparison of effect sizes between pharmacogenomic and non-pharmacogenomic phenotypes across all genome-wide association studies (GWAS) reported in the NHGRI GWAS catalog. We found significantly larger effect sizes for studies focused on pharmacogenomic phenotypes, as compared with complex disease risk, morphological phenotypes and endophenotypes. We found no significant differences in effect sizes between pharmacogenomic studies focused on adverse events versus those focused on drug efficacy. Furthermore, we found that this pattern persists among sample size-matched studies, suggesting that this pattern does not reflect overestimation of effect sizes due to smaller sample sizes in pharmacogenomic studies.The Pharmacogenomics Journal advance online publication, 7 July 2015; doi:10.1038/tpj.2015.47.
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12 MeSH Terms
Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age.
Zannas AS, McQuoid DR, Payne ME, MacFall JR, Ashley-Koch A, Steffens DC, Potter GG, Taylor WD
(2014) Am J Psychiatry 171: 1214-21
MeSH Terms: Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Cognition Disorders, Endophenotypes, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Hippocampus, Humans, Linkage Disequilibrium, Male, Memory, Episodic, Middle Aged, Organ Size, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1, Renin-Angiotensin System
Show Abstract · Added February 4, 2016
OBJECTIVE - Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus.
METHOD - The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype.
RESULTS - Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss.
CONCLUSIONS - Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.
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20 MeSH Terms
Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay.
Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, Malow BA
(2015) J Autism Dev Disord 45: 100-10
MeSH Terms: Acetylserotonin O-Methyltransferase, Child, Child Development Disorders, Pervasive, Child, Preschool, Clinical Trials as Topic, Cytochrome P-450 CYP1A2, DNA Mutational Analysis, Endophenotypes, Genotype, Humans, Male, Melatonin, Mutation, Polymorphism, Single Nucleotide, Sleep Initiation and Maintenance Disorders
Show Abstract · Added February 12, 2015
Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with comorbid expression of sleep onset delay. We evaluated variation in two melatonin pathway genes, acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2). We observed higher frequencies than currently reported (p < 0.04) for variants evidenced to decrease ASMT expression and related to decreased CYP1A2 enzyme activity (p ≤ 0.0007). We detected a relationship between genotypes in ASMT and CYP1A2 (r(2) = 0.63). Our results indicate that expression of sleep onset delay relates to melatonin pathway genes.
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15 MeSH Terms