BackgroundIndividual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol.ResultsAcute ethanol altered the expression of ∼2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity.Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2.ConclusionsThe ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders.

Previous research has demonstrated stability of cognitive ability and marked heritability during adulthood, but questions remain about the extent to which genetic factors account for this stability. We conducted a 35-year longitudinal assessment of general cognitive ability using the Armed Forces Qualification Test administered to 7,232 male twins in early adulthood and readministered to a subset of 1,237 twins during late middle age. The proportion of variance in cognitive functioning explained by genetic factors in young adulthood was .49 and it was .57 in late middle age. The correlation between the two administrations was .74 with a genetic correlation of 1.0, indicating that the same genetic influences operated at both times. Genetic factors were primarily responsible for stability and nonshared environmental factors for change. The genetic factors influencing cognition may change across other eras, but the same genetic influences are operating from early adulthood to late middle-age.Spearman described a general factor common to many mental abilities that he called "g" (Neisser et al., 1996), which accounts for at least 50% of the variance across a range of mental tests and is one of the most replicated findings in psychology (Neisser et al., 1996). General cognitive ability correlates with numerous other characteristics, such as academic and occupational success (Neisser et al., 1996). There has been very little longitudinal, genetically informative research that addresses this trait during the period from early adulthood to late-middle adulthood, a period that has been quite understudied in many domains. There are three important questions about general cognitive ability during this period: What are the magnitudes of genetic and environmental influences during this period? Do the same or different genetic and environmental influences operate at different ages? Finally, what are the genetic and environmental influences on change and stability over time? To answer these questions unambiguously, a study must have longitudinal data, a long time interval, the same measure at each assessment, and a genetically informative sample.Address correspondence to Michael J. Lyons, Department of Psychology, 64 Cummington St., Boston, MA, mlyons@bu.edu. To our knowledge, no study to date has met all of these criteria. Midlife remains a sorely understudied period, with the bulk of developmental research investigating childhood, adolescence, or old age. Most of the extant genetically informative studies are crosssectional, and the few longitudinal studies cover relatively short time intervals. In many studies, different measures of g are used at different ages, and each measure will have its own unique method variance. NIH Public Access What are the Magnitudes of Genetic and Environmental Influences DuringThis Period? Bouchard and McGue (2003) reviewed the behavioral genetics studies of cognitive ability and suggested that the relative strength of genetic and environmental influences on intelligence varies with age....

Genome wide complex trait analysis (GCTA) is extended to include environmental effects of the maternal genotype on offspring phenotype (“maternal effects”, M-GCTA). The model includes parameters for the direct effects of the offspring genotype, maternal effects and the covariance between direct and maternal effects. Analysis of simulated data, conducted in OpenMx, confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored. Estimates derived from FIML in OpenMx showed very close agreement to those obtained by restricted maximum likelihood using the published algorithm for GCTA. The method was also applied to illustrative perinatal phenotypes from ∼4,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children. The relative merits of extended GCTA in contrast to quantitative genetic approaches based on analyzing the phenotypic covariance structure of kinships are considered.

Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (eg, CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (eg, DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (ie, intraamniotic infection) or "danger signals" (alarmins) released during cellular stress or necrosis (ie, sterile intraamniotic inflammation). These findings support the notion that preterm birth has a polygenic basis that involves rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the whole exome sequencing-identified genes and other inflammatory conditions associated with preterm birth, such as periodontal disease and inflammatory bowel disease, was observed, which suggests a shared genetic substrate for these conditions. We propose that whole exome sequencing, as well as whole genome sequencing, is the most promising approach for the identification of functionally signi...

The overall mean response to montelukast may be skewed towards a response phenotype by a small subset (<15%) of asthma patients. CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations, yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy. These findings require replication to establish validity and clinical utility.