Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

http://ibgwww.colorado.edu/cdrom2009/ScriptsA/purcell/GWAS/boulder_09_plink_intro.pdf

PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

Background Little is known about the general population prevalence or severity of DSM-IV mental disorders. Objective To estimate 12-month prevalence, severity, and comorbidity of DSM-IV anxiety, mood, impulse control, and substance disorders in the recently completed US National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using a fully structured diagnostic interview, the World Health Organization World Mental Health Survey Initiative version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents 18 years and older. Main Outcome Measures Twelve-month DSM-IV disorders. Results Twelve-month prevalence estimates were anxiety, 18.1%; mood, 9.5%; impulse control, 8.9%; substance, 3.8%; and any disorder, 26.2%. Of 12-month cases, 22.3% were classified as serious; 37.3%, moderate; and 40.4%, mild. Fifty-five percent carried only a single diagnosis; 22%, 2 diagnoses; and 23%, 3 or more diagnoses. Latent class analysis detected 7 multivariate disorder classes, including 3 highly comorbid classes representing 7% of the population. Conclusion Although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of cases with high comorbidity.

/pdf/prevalence-severity-and-comorbidity-of-12-month-dsm-iv-54fahxwd1s.pdf

Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication

W. Wilson's (1967) review of the area of subjective well-being (SWB) advanced several conclusions regarding those who report high levels of "happiness". A number of his conclusions have been overturned: youth and modest aspirations no longer are seen as prerequisites of SWB. E. Diener's (1984) review placed greater emphasis on theories that stressed psychological factors. In the current article, the authors review current evidence for Wilson's conclusions and discuss modern theories of SWB that stress dispositional influences, adaptation, goals, and coping strategies. The next steps in the evolution of the field are to comprehend the interaction of psychological factors with life circumstances in producing SWB, to understand the causal pathways leading to happiness, understand the processes underlying adaptation to events, and develop theories that explain why certain variables differentially influence the different components of SWV (life satisfaction, pleasant affect, and unpleasant affect).

Subjective Well-Being: Three Decades of Progress

There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

/pdf/genome-wide-association-study-of-14-000-cases-of-seven-5ay7q0q3vy.pdf

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

W Wilson's (1967) review of the area of subjective well-being (SWB) advanced several conclusions regarding those who report high levels of "happiness" A number of his conclusions have been overturned: youth and modest aspirations no longer are seen as prerequisites of SWB E Diener's (1984) review placed greater emphasis on theories that stressed psychological factors In the current article, the authors review current evidence for Wilson's conclusions and discuss modern theories of SWB that stress dispositional influences, adaptation, goals, and coping strategies The next steps in the evolution of the field are to comprehend the interaction of psychological factors with life circumstances in producing SWB, to understand the causal pathways leading to happiness, understand the processes underlying adaptation to events, and develop theories that explain why certain variables differentially influence the different components of SWB (life satisfaction, pleasant affect, and unpleasant affect) In 1967, Warner Wilson presented a broad review of subjective well-being (SWB) research entitled, "Correlates of Avowed Happiness" Based on the limited data available at that time, Wilson concluded that the happy person is a "young, healthy, welleducated, well-paid, extroverted, optimistic, worry-free, religious, married person with high self-esteem, job morale, modest aspirations, of either sex and of a wide range of intelligence" (p 294) In the three decades since Wilson's review, investigations into SWB have evolved Although researchers now know a great deal more about the correlates of SWB, they are less interested in simply describing the demographic characteristics that correlate with it Instead, they focus their effort on understanding the processes that underlie happiness This trend represents a greater recognition of the central role played by people's goals, coping efforts, and dispositions In this article, we review research on several major theoretical approaches to well-being and then indicate how these theories clarify the findings on demographic correlates of SWB Throughout the review we suggest four directions that researchers should pursue in the decades ahead These are by no means the only questions left to answer, but we believe they are the most interesting issues left to resolve First, the causal direction of the correlates of happiness must be examined through more sophisticated methodologies Although the causal priority of demographic factors such as marriage and income is intuitively appealing, it is by no means certain Second, researchers must focus greater attention on the interaction between internal factors (such as personality traits) and external circumstances As we shall see, demographic factors have surprisingly small effects on SWB, but these effects may depend on the personalities of those individuals being studied Thus, future research must take Person X Situation interactions into account Third, researchers must strive to understand the processes underlying adaptation Considerable adaptation to both good and bad circumstances often occurs, yet the processes responsible for these effects are poorly understood Research that examines how habituation, coping strategies, and changing goals influence adaptation will shed much light on the processes responsible for SWB Finally, theories must be refined to make specific predictions about how input variables differentially influence the components of SWB In the past, many researchers have treated SWB as a monolithic entity, but it is now clear that there are separable components that exhibit unique patterns of relations with different variables In each section of this article we discuss progress and opportunities in these four areas

/pdf/subjective-well-being-three-decades-of-progress-55l9oy0irc.pdf

Subjective well-being: Three decades of progress

Comparison of the effects of season and prematurity on the enzymatic newborn screening tests for galactosemia and biotinidase deficiency

The present invention is based at least in part on the discovery of polymorphisms within the 5-lipoxygenase gene which are included in a haplotype. Accordingly, the invention provides nucleic acid molecules having a nucleotide sequence of an allelic variant of a 5-LO gene. The invention also provides methods for identifying specific alleles of polymorphic regions of a 5-LO gene, methods for determining whether a patient has a more or less severe phenotype of an inflammatory disease or disorder such as asthma, methods for determining whether a patient will be more or less responsive to treatment with 5′LO inhibitors, forensic methods based on detection of polymorphisms within the 5-LO gene, and kits for performing such methods.

Detection of polymorphisms in the human 5-lipoxygenase gene

Another view on the 'right' statistical measure of twin concordance.

1 Abstract: Pharmacologic agents such as hydroxyurea (HU), N, 3-4 trihydroxybenzamide (didox), and isobutyramide (ISB) can elevate γ-globin as a potential treatment for the β-hemoglobinopathies. In these experiments, transgenic mice with 5'HS2 from the human β-globin locus control region, the fetal ( A γ), and adult (β s ) globin genes were used. Mice were treated with HU, didox, or ISB individually, or with combinations of HU or didox with ISB. The aim was to determine whether these drugs have synergistic effects on the induction of fetal hemoglobin (HbF) and whether the combination regimens are more hematotoxic. In the combination regimens, injections of HU or didox for five weeks were concomitant with ISB treatment every other day for the final three weeks of treatment. The combination of HU+ISB was more hematotoxic than the individual drugs based on significantly increased percentages of reticulocytes and reduced hemoglobin, indicating that caution should be taken in treatments involving combinations of these types of drugs. The didox+ISB combination was not more hematotoxic than the individual drugs. HbF was not induced in the groups treated with the combinations of HU or didox with ISB compared to the individual agents. There was a negligible effect on the percentage of HbF and an unexpected negative effect on the percentage of F cells. The results also have implications for future testing of HbF- inducing drugs in mouse models. In control mice that were phlebotomized but not treated with any drugs, increased percentages of F cells were observed, indicating that blood sampling can cause this effect. In addition, increases in the percentage of F cells did not correlate with increases in the percentage of HbF, indicating that monitoring F cells alone is not a sufficient measure of HbF induction.

A Combination of Hydroxyurea and Isobutyramide to Induce Fetal Hemoglobin in Transgenic Mice Is More Hematotoxic Than the Individual Agents

Comparative ratings between pairs of siblings or other relatives are commonly used to refine measures of intrafamily variation. A simple model, based on signal detection theory, is proposed which shows how comparative ratings can be used to estimate within-pair variances of true scores, which can, in turn, be modeled with any of the conventional approaches to partitioning genetic and environmental variance within families.

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Joanne M. Meyer

Papers

Comparison of the effects of season and prematurity on the enzymatic newborn screening tests for galactosemia and biotinidase deficiency

Detection of polymorphisms in the human 5-lipoxygenase gene

Another view on the 'right' statistical measure of twin concordance.

A Combination of Hydroxyurea and Isobutyramide to Induce Fetal Hemoglobin in Transgenic Mice Is More Hematotoxic Than the Individual Agents

A Model for Comparative Ratings in Studies of Within-Family Differences