A Three-Stage Genome-Wide Association Study of General Cognitive Ability: Hunting the Small Effects

Childhood general cognitive ability (g) is important for a wide range of outcomes in later life, from school achievement to occupational success and life expectancy. Large-scale association studies will be essential in the quest to identify variants that make up the substantial genetic component implicated by quantitative genetic studies. We conducted a three-stage genome-wide association study for general cognitive ability using over 350,000 single nucleotide polymorphisms (SNPs) in the quantitative extremes of a population sample of 7,900 7-year-old children from the UK Twins Early Development Study. Using two DNA pooling stages to enrich true positives, each of around 1,000 children selected from the extremes of the distribution, and a third individual genotyping stage of over 3,000 children to test for quantitative associations across the normal range, we aimed to home in on genes of small effect. Genome-wide results suggested that our approach was successful in enriching true associations and 28 SNPs were taken forward to individual genotyping in an unselected population sample. However, although we found an enrichment of low P values and identified nine SNPs nominally associated with g (P < 0.05) that show interesting characteristics for follow-up, further replication will be necessary to meet rigorous standards of association. These replications may take advantage of SNP sets to overcome limitations of statistical power. Despite our large sample size and three-stage design, the genes associated with childhood g remain tantalizingly beyond our current reach, providing further evidence for the small effect sizes of individual loci. Larger samples, denser arrays and multiple replications will be necessary in the hunt for the genetic variants that influence human cognitive ability

Sickness presenteeism determines job satisfaction via affective-motivational states

Research on the consequences of sickness presenteeism, or the phenomenon of attending work whilst ill, has focused predominantly on identifying its economic, health, and absenteeism outcomes, neglecting important attitudinal-motivational outcomes. A mediation model of sickness presenteeism as a determinant of job satisfaction via affective-motivational states (specifically engagement with work and addiction to work) is proposed. This model adds to the current literature, by focusing on (i) job satisfaction as an outcome of presenteeism, and (ii) the psychological processes associated with this. It posits presenteeism as psychological absence and work engagement and work addiction as motivational states that originate in that. An online survey was completed by 158 office workers on sickness presenteeism, work engagement, work addiction, and job satisfaction. The results of bootstrapped mediation analysis with observable variables supported the model. Sickness presenteeism was negatively associated with job satisfaction. This relationship was fully mediated by both engagement with work and addiction to work, explaining a total of 48.07% of the variance in job satisfaction. Despite the small sample, the data provide preliminary support for the model. Given that there is currently no available research on the attitudinal consequences of presenteeism, these findings offer promise for advancing theorising in this area

Integrating tropical research into biology education is urgently needed

Understanding tropical biology is important for solving complex problems such as climate change, biodiversity loss, and zoonotic pandemics, but biology curricula view research mostly via a temperatezone lens. Integrating tropical research into biology education is urgently needed to tackle these issues. The tropics are engines of Earth systems that regulate global cycles of carbon and water, and are thus critical for management of greenhouse gases. Compared with higher-latitude areas, tropical regions contain a greater diversity of biomes, organisms, and complexity of biological interactions. The tropics house the majority of the world’s human population and provide important global commodities from species that originated there: coffee, chocolate, palm oil, and species that yield the cancer drugs vincristine and vinblastine. Tropical regions, especially biodiversity hotspots, harbor zoonoses, thereby having an important role in emerging infectious diseases amidst the complex interactions of global environmental change and wildlife migration [1]. These well-known roles are oversimplified, but serve to highlight the global biological importance of tropical systems. Despite the importance of tropical regions, biology curricula worldwide generally lack coverage of tropical research. Given logistical, economic, or other barriers, it is difficult for undergraduate biology instructors to provide their students with field-based experience in tropical biology research in a diverse range of settings, an issue exacerbated by the Coronavirus Disease 2019 (COVID-19) pandemic. Even in the tropics, field-based experience may be limited to home regions. When tropical biology is introduced in curricula, it is often through a temperate- zone lens that does not do justice to the distinct ecosystems, sociopolitical histories, and conservation issues that exist across tropical countries and regions [2]. The tropics are often caricatured as distant locations known for their remarkable biodiversity, complicated species interactions, and unchecked deforestation. This presentation, often originating from a colonial and culturally biased perspective, may fail to highlight the role of tropical ecosystems in global environmental and social challenges that accompany rising temperatures, worldwide biodiversity loss, zoonotic pandemics, and the environmental costs of ensuring food, water, and other ecosystem services for humans [3]

Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genome-wide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity

The Lothian Birth Cohort 1936: a study to examine influences on cognitive ageing from age 11 to age 70 and beyond

BACKGROUND: Cognitive ageing is a major burden for society and a major influence in lowering people's independence and quality of life. It is the most feared aspect of ageing. There are large individual differences in age-related cognitive changes. Seeking the determinants of cognitive ageing is a research priority. A limitation of many studies is the lack of a sufficiently long period between cognitive assessments to examine determinants. Here, the aim is to examine influences on cognitive ageing between childhood and old age. METHODS/DESIGN: The study is designed as a follow-up cohort study. The participants comprise surviving members of the Scottish Mental Survey of 1947 (SMS1947; N = 70,805) who reside in the Edinburgh area (Lothian) of Scotland. The SMS1947 applied a valid test of general intelligence to all children born in 1936 and attending Scottish schools in June 1947. A total of 1091 participants make up the Lothian Birth Cohort 1936. They undertook: a medical interview and examination; physical fitness testing; extensive cognitive testing (reasoning, memory, speed of information processing, and executive function); personality, quality of life and other psycho-social questionnaires; and a food frequency questionnaire. They have taken the same mental ability test (the Moray House Test No. 12) at age 11 and age 70. They provided blood samples for DNA extraction and testing and other biomarker analyses. Here we describe the background and aims of the study, the recruitment procedures and details of numbers tested, and the details of all examinations. DISCUSSION: The principal strength of this cohort is the rarely captured phenotype of lifetime cognitive change. There is additional rich information to examine the determinants of individual differences in this lifetime cognitive change. This protocol report is important in alerting other researchers to the data available in the cohort

Coming to terms with heritability

The complex mechanisms of heredity are little appreciated by non-specialists, in some measure, because of misunderstandings that are perpetuated when words used for technical terms have other, more widely understood, folk meanings. When a word has both technical and folk meanings, it is the responsibility of the specialist to avoid promoting confusion by either using extremely cautious and precise language when using the term or, in cases when confusion is inevitable, abandoning the term in favor of one without a widely understood folk meaning. The study of heredity is beset by such confusion, and the term heritability appears to be at the heart of some of the confusion. In this article, I discuss both the technical and folk meanings of heritability and examine the bridge between them. By continuing to use the term heritability, we risk promulgating serious misunderstanding about the workings of heredity, therefore I suggest selectability as an alternative term to avoid such pitfalls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42804/1/10709_2005_Article_BF02259512.pd

Treatment- and Population-Dependent Activity Patterns of Behavioral and Expression QTLs

Genetic control of gene expression and higher-order phenotypes is almost invariably dependent on environment and experimental conditions. We use two families of recombinant inbred strains of mice (LXS and BXD) to study treatment- and genotype-dependent control of hippocampal gene expression and behavioral phenotypes. We analyzed responses to all combinations of two experimental perturbations, ethanol and restraint stress, in both families, allowing for comparisons across 8 combinations of treatment and population. We introduce the concept of QTL activity patterns to characterize how associations between genomic loci and traits vary across treatments. We identified several significant behavioral QTLs and many expression QTLs (eQTLs). The behavioral QTLs are highly dependent on treatment and population. We classified eQTLs into three groups: cis-eQTLs (expression variation that maps to within 5 Mb of the cognate gene), syntenic trans-eQTLs (the gene and the QTL are on the same chromosome but not within 5 Mb), and non-syntenic trans-eQTLs (the gene and the QTL are on different chromosomes). We found that most non-syntenic trans-eQTLs were treatment-specific whereas both classes of syntenic eQTLs were more conserved across treatments. We also found there was a correlation between regions along the genome enriched for eQTLs and SNPs that were conserved across the LXS and BXD families. Genes with eQTLs that co-localized with the behavioral QTLs and displayed similar QTL activity patterns were identified as potential candidate genes associated with the phenotypes, yielding identification of novel genes as well as genes that have been previously associated with responses to ethanol

Statistical Epistasis and Functional Brain Imaging Support a Role of Voltage-Gated Potassium Channels in Human Memory

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed “missing heritability.” The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (Pnominal combined = 0.000001). The epistatic interaction was robust, as it was significant in a screening (Pnominal = 0.0000012) and in a replication sample (Pnominal = 0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (Pnominal = 0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits

Genomic Analysis of Individual Differences in Ethanol Drinking: Evidence for Non-Genetic Factors in C57BL/6 Mice

Genetic analysis of factors affecting risk to develop excessive ethanol drinking has been extensively studied in humans and animal models for over 20 years. However, little progress has been made in determining molecular mechanisms underlying environmental or non-genetic events contributing to variation in ethanol drinking. Here, we identify persistent and substantial variation in ethanol drinking behavior within an inbred mouse strain and utilize this model to identify gene networks influencing such “non-genetic” variation in ethanol intake. C57BL/6NCrl mice showed persistent inter-individual variation of ethanol intake in a two-bottle choice paradigm over a three-week period, ranging from less than 1 g/kg to over 14 g/kg ethanol in an 18 h interval. Differences in sweet or bitter taste susceptibility or litter effects did not appreciably correlate with ethanol intake variation. Whole genome microarray expression analysis in nucleus accumbens, prefrontal cortex and ventral midbrain region of individual animals identified gene expression patterns correlated with ethanol intake. Results included several gene networks previously implicated in ethanol behaviors, such as glutamate signaling, BDNF and genes involved in synaptic vesicle function. Additionally, genes functioning in epigenetic chromatin or DNA modifications such as acetylation and/or methylation also had expression patterns correlated with ethanol intake. In verification for the significance of the expression findings, we found that a histone deacetylase inhibitor, trichostatin A, caused an increase in 2-bottle ethanol intake. Our results thus implicate specific brain regional gene networks, including chromatin modification factors, as potentially important mechanisms underlying individual variation in ethanol intake