The genetic architecture of type 2 diabetes.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Risk factors affecting injury severity determined by the MAIS score

Objective: Traffic crashes result in a loss of life but also impact the quality of life and productivity of crash survivors. Given the importance of traffic crash outcomes, the issue has received attention from researchers and practitioners as well as government institutions, such as the European Commission (EC). Thus, to obtain detailed information on the injury type and severity of crash victims, hospital data have been proposed for use alongside police crash records. A new injury severity classification based on hospital data, called the maximum abbreviated injury scale (MAIS), was developed and recently adopted by the EC. This study provides an in-depth analysis of the factors that affect injury severity as classified by the MAIS score.Method: In this study, the MAIS score was derived from the International Classification of Diseases. The European Union adopted an MAIS score equal to or greater than 3 as the definition for a serious traffic crash injury. Gains are expected from using both police and hospital data because the injury severities of the victims are detailed by medical staff and the characteristics of the crash and the site of its occurrence are also provided. The data were obtained by linking police and hospital data sets from the Porto metropolitan area of Portugal over a 6-year period (2006-2011). A mixed logit model was used to understand the factors that contribute to the injury severity of traffic victims and to explore the impact of these factors on injury severity. A random parameter approach offers methodological flexibility to capture individual-specific heterogeneity. Additionally, to understand the importance of using a reliable injury severity scale, we compared MAIS with length of hospital stay (LHS), a classification used by several countries, including Portugal, to officially report injury severity. To do so, the same statistical technique was applied using the same variables to analyze their impact on the injury severity classified according to LHS.Results: This study showed the impact of variables, such as the presence of blood alcohol, the use of protection devices, the type of crash, and the site characteristics, on the injury severity classified according to the MAIS score. Additionally, the sex and age of the victims were analyzed as risk factors, showing that elderly and male road users are highly associated with MAIS 3+ injuries. The comparison between the marginal effects of the variables estimated by the MAIS and LHS models showed significant differences. In addition to the differences in the magnitude of impact of each variable, we found that the impact of the road environment variable was dependent on the injury severity classification.Conclusions: The differences in the effects of risk factors between the classifications highlight the importance of using a reliable classification of injury severity. Additionally, the relationship between LHS and MAIS levels is quite different among countries, supporting the previous conclusion that bias is expected in the assessment of risk factors if an injury severity classification other than MAIS is used