Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Acceptance testing for road surface monitoring vehicles in Finland

VTI has carried out acceptance testing of companies that would like to do road surface monitoring in Finland. This has been done on commission of the Finnish Road Administration. This kind of acceptance testing has been done in Sweden by VTI in cooperation with the Swedish Road Administration several times (four times). With the experience of the tests in Sweden a test method adjusted for the Finnish needs have been composed. The purpose of the method is to accept or reject the participating companies for doing either object or network measurements or both. This is done by checking the validity and repeatability for the object part and the reproducibility for the network part. The tests for the object part involve measurements at test sections including measuring with reference methods as well as repeated measurements on a route. For the reproducibility test, done at the network measuring acceptance, runs with different combinations of vehicles and drivers/operators are carried out. The tests give answers to questions like: - The technical skill to measure according to the procurement specifications. - The ability and type of organisation to take care of and process data under given circumstances like this test. - The ability to deliver data of right quality in time. To be accepted as a contractor of network level measurements the company also has to be accepted for object measurements

Litteraturöversikt över aldehyders biologiska effekter, förekomst i arbetsmiljön och mätmetoder.

Formaldehyds allergiframkallande och ev cancerframkallande egenskaper har fäst uppmärksamheten på gruppen aldehyder, i vilken formaldehyd ingår. Gruppen aldehyder har det gemensamt att de flesta är irriterande för ögon och slemhinnor. Några av aldehyderna är dessutom allergiframkallande. För de flesta aldehyder finns inte tillräckliga kunskaper för att avgöra om de kan framkalla cancer eller fosterskador. Aldehyder används i de flesta branscher och ofta på ett sådant sätt att människor kommer i kontakt med aldehyder. Rapporten beskriver på ett lättbegripligt sätt - olika aldehyder och deras användningsområde, - biologiska effekter av aldehyder, - halter av aldehyder i arbetsmiljön, - gränsvärden, regler och normer. I rapportens sista kapitel anges vad man kan göra för att minska kontakten med aldehyder i arbetsmiljön.Formaldehyds allergiframkallande och ev cancerframkallande egenskaper har fäst uppmärksamheten på gruppen aldehyder, i vilken formaldehyd ingår. Gruppen aldehyder har det gemensamt att de flesta är irriterande för ögon och slemhinnor. Några av aldehyderna är dessutom allergiframkallande. För de flesta aldehyder finns inte tillräckliga kunskaper för att avgöra om de kan framkalla cancer eller fosterskador. Aldehyder används i de flesta branscher och ofta på ett sådant sätt att människor kommer i kontakt med aldehyder. Rapporten beskriver på ett lättbegripligt sätt - olika aldehyder och deras användningsområde, - biologiska effekter av aldehyder, - halter av aldehyder i arbetsmiljön, - gränsvärden, regler och normer. I rapportens sista kapitel anges vad man kan göra för att minska kontakten med aldehyder i arbetsmiljön

Disappearing sensor : Textile based sensor for monitoring breathing

The monitoring and interpretation of respiration pattern plays an important role for the early detection and the prevention of serious illness, such as asthma, sleeping apnea, bronchitis, and lung cancer. In this interdisciplinary project a system based on a smart shirt with integrated textile sensor for personal respiratory monitoring was developed. Due to the fact that textile products are flexible, washable and bring no discomfort to wearers, the smart shirtis an excellent interface for performing long term respiratory monitoring in real life situations outside the clinic. Two stripe liked sensors located on the chest and abdomen position respectively were integrated in a smart shirt. The sensors were made by coating with conductive silicone on the fabric surface of the smart shirt. Conductive silicone reflects compression or extension by resistance change and in this application resistance change can be utilized to indicate the respiratory pattern of the wearer. A prototype system was made to record the resistance change in real time and transmission to a PC or PDA for further processing. Snap button and conductive threads were used as the interface and transmission wires between the smart shirt and the recording system. To verify the performance, test were made with 10 subjects, whose spontaneous respiratory patterns were recorded during sitting still, walking and jogging. In addition, a number of abnormal respiratory conditions, such as deep breathing, hyperventilation and sleeping apnea were simulated. The results show the smart shirt performed in a very good manner, the system can sense and record the person&apos;s breathing during normal daily activities. The sleeping apnea simulation indicates potential application in diagnosis and clinical treatment. The smart shirt is soft and comfortable to use and enables long-term monitoring to be performed outside the laboratory

Road user effect models : the influence of rut depth on traffic safety

Det saknas idag tillfredsställande effektmodeller för beräkning av konsekvenser och kostnader för trafikanterna av olika underhållsstrategier. Det största problemet identifierat av Trafikverken/Vägverken i Finland, Sverige, Norge och Estland är sambandet mellan vägytans tillstånd och olyckor, effekten av den viktigaste tillståndsparametern spårdjup för trafikantkostnaderna, liksom betydelsen av trafikantkostnaderna/- effekterna för ett vägnät som är i ett huvudsakligen gott tillstånd. Detta är problem som måste lösas för att bättre kunna rättfärdiga budgettilldelningen för vägunderhåll. VTI har därför i uppdrag på finska Trafikverket och med finansiering även från de övriga Trafikverken/Vägverken, genomfört en studie för att avgöra hur spårdjup påverkar olycksrisken för trafikanter. Separata analyser har gjorts för data från Sverige, Finland respektive Norge. Det antogs att olycksrisken också beror på andra vägtillståndsvariabler, t.ex. längsgående ojämnhet, textur, tvärfall, geografiskt läge (land), fordonsflöde, klimat, väderförhållanden etc. En modellansats valdes som skulle kunna hantera påverkan av alla dessa övriga vägtillståndsvariabler, samt eventuella interaktioner mellan dessa, på olycksrisken. Det antogs vidare att förhållandet mellan olycksrisk och spårdjup inte nödvändigtvis är en linjär funktion, varför spårdjup delades upp i ett antal kategorier. Det beslutades också att separata ekvationer skulle härledas för olika hastighets- och ÅDT (Årsmedeldygnstrafiken)-klasser. Spårdjupskategorier samt hastighets- och ÅDT-klasser valdes för att matcha varje lands strategier för underhåll. Den övergripande slutsatsen av analysen är att data inte ger stöd för några allmänna regler i en underhållsplan. Det finns inga resultat från studien som säger att djupare spår generellt tenderar att öka olycksrisken. Det finns heller inga resultat som säger att spår har samma påverkan på olycksrisken i olika ÅDT-klasser vid en given hastighet eller vice versa. Det tycks finnas en ökad risk vid spårdjup ? ca 15 mm i högsta hastighetsklassen, men resultaten skiljer sig åt mellan olika ÅDT-klasser och inte är lika i angränsande hastighetsklasser, vilket gör resultaten svåra att förstå och mindre användbara för att ange regler för underhåll. För norska data erhölls inte samma resultat i den högsta hastighetsklassen (&gt; =90 km/tim), denna skiljer sig dock från de svenska och finska högsta hastighetsklasserna (&gt; =110 km/tim-vägar respektive motorväg)There are currently no satisfactory effect models for calculating the consequences and costs for road users of different maintenance strategies. The main problems identified by the Transport/Road Administrations in Finland, Sweden, Norway and Estonia, are the relationship between road surface condition and accidents, the effect of the most important state parameter rut depth on road user costs, as well as the role of road-user costs/effects of a road network that is mostly in good condition. These are problems that must be resolved in order to better justify budget allocation for road maintenance. VTI has therefore on commission by the Finnish Transport Administration and with funding from the other Transport/Road Administrations conducted a study to determine the influence of rut depth effects on the accident risk of road users. Separate analyses were made of data from Sweden, Finland and Norway, respectively. It was assumed that the accident risk also depends on other road condition variables, such as longitudinal unevenness, texture, cross slope, geographic location (country), vehicle flow, climate, weather, etc. A model approach was chosen that could address the impact of all these other road condition variables, and the possible interactions between them, on the accident risk. It was assumed that the relationship between accident risk and rut depth is not necessarily a linear function, why rut depth was divided into several categories. It was also agreed that separate equations should be derived for different speed and AADT (Annual average daily traffic) classes. Rut depth categories, as well as speed and AADT classes were chosen to match each country's strategies for maintenance. The overall conclusion of the analysis is that the data does not support any general rules for a maintenance scheme. There are no results to show that deeper ruts generally tend to increase the accident risk. Nor are there results that show that ruts have the same influence on the accident risk for different AADT classes at a given speed or vice versa. There seems to be at increased risk for ruts ? about 15 mm in the highest speed class, but the results differ between AADT classes and are not similar in adjacent speed classes, making the results difficult to understand and less useful to specify the rules for maintenance. For the Norwegian data this trend can not be seen in the highest speed class (&gt; = 90 km/h), but then this speed class differs from the Swedish and Finnish highest speed classes (&gt; = 110 km/h roads and motorways, respectively)

Disappearing sensor : Textile based sensor for monitoring breathing

The monitoring and interpretation of respiration pattern plays an important role for the early detection and the prevention of serious illness, such as asthma, sleeping apnea, bronchitis, and lung cancer. In this interdisciplinary project a system based on a smart shirt with integrated textile sensor for personal respiratory monitoring was developed. Due to the fact that textile products are flexible, washable and bring no discomfort to wearers, the smart shirtis an excellent interface for performing long term respiratory monitoring in real life situations outside the clinic. Two stripe liked sensors located on the chest and abdomen position respectively were integrated in a smart shirt. The sensors were made by coating with conductive silicone on the fabric surface of the smart shirt. Conductive silicone reflects compression or extension by resistance change and in this application resistance change can be utilized to indicate the respiratory pattern of the wearer. A prototype system was made to record the resistance change in real time and transmission to a PC or PDA for further processing. Snap button and conductive threads were used as the interface and transmission wires between the smart shirt and the recording system. To verify the performance, test were made with 10 subjects, whose spontaneous respiratory patterns were recorded during sitting still, walking and jogging. In addition, a number of abnormal respiratory conditions, such as deep breathing, hyperventilation and sleeping apnea were simulated. The results show the smart shirt performed in a very good manner, the system can sense and record the person&apos;s breathing during normal daily activities. The sleeping apnea simulation indicates potential application in diagnosis and clinical treatment. The smart shirt is soft and comfortable to use and enables long-term monitoring to be performed outside the laboratory

Adaptive spatio-temporal filtering of disturbed ECGs: a multi-channel approach to heartbeat detection in smart clothing

Intermittent disturbances are common in ECG signals recorded with smart clothing: this is mainly because of displacement of the electrodes over the skin. We evaluated a novel adaptive method for spatio-temporal filtering for heartbeat detection in noisy multi-channel ECGs including short signal interruptions in single channels. Using multi-channel database recordings (12-channel ECGs from 10 healthy subjects), the results showed that multi-channel spatio-temporal filtering outperformed regular independent component analysis. We also recorded seven channels of ECG using a T-shirt with textile electrodes. Ten healthy subjects performed different sequences during a 10-min recording: resting, standing, flexing breast muscles, walking and pushups. Using adaptive multi-channel filtering, the sensitivity and precision was above 97% in nine subjects. Adaptive multi-channel spatio-temporal filtering can be used to detect heartbeats in ECGs with high noise levels. One application is heartbeat detection in noisy ECG recordings obtained by integrated textile electrodes in smart clothing

Radical Prostatectomy, Sparing of the Seminal Vesicles, and Painful Orgasm.

INTRODUCTION: Erectile dysfunction has been widely investigated as the major factor responsible for sexual bother in patients after radical prostatectomy (RP); painful orgasm (PO) is one element of this bother, but little is known about its prevalence and its effects on sexual health. AIM: This study aims to investigate the prevalence of PO and to identify potential risk factors. MAIN OUTCOME MEASURES: A total of 1,411 consecutive patients underwent open (radical retropubic prostatectomy) or robot-assisted laparoscopic RP between 2002 and 2006. The patients were asked to complete a study-specific questionnaire. METHODS: Of a total of 145 questions, 5 dealt with the orgasmic characteristics. The questionnaire was also administered to a comparison group of 442 persons, matched for age and area of residency. RESULTS: The response rate was 91% (1,288 patients). A total of 143 (11%) patients reported PO. Among the 834 men being able to have an orgasm, the prevalence was 18% vs. 6% in the comparison group (relative risk [RR] 2.8, 95% confidence interval [CI] 1.7-4.5). When analyzed as independent variables, bilateral seminal vesicle (SV)-sparing approach (RR 2.33, 95% CI 1.0-5.3, P = 0.045) and ag

Radical Prostatectomy, Sparing of the Seminal Vesicles, and Painful Orgasm

Introduction Erectile dysfunction has been widely investigated as the major factor responsible for sexual bother in patients after radical prostatectomy (RP); painful orgasm (PO) is one element of this bother, but little is known about its prevalence and its effects on sexual health. Aim This study aims to investigate the prevalence of PO and to identify potential risk factors. Main Outcome Measures A total of 1,411 consecutive patients underwent open (radical retropubic prostatectomy) or robot-assisted laparoscopic RP between 2002 and 2006. The patients were asked to complete a study-specific questionnaire. Methods Of a total of 145 questions, 5 dealt with the orgasmic characteristics. The questionnaire was also administered to a comparison group of 442 persons, matched for age and area of residency. Results The response rate was 91% (1,288 patients). A total of 143 (11%) patients reported PO. Among the 834 men being able to have an orgasm, the prevalence was 18% vs. 6% in the comparison group (relative risk [RR] 2.8, 95% confidence interval [CI] 1.74.5). When analyzed as independent variables, bilateral seminal vesicle (SV)-sparing approach (RR 2.33, 95% CI 1.05.3, P=0.045) and age &lt;60 years were significantly related to the presence of PO (95% CI 0.50.9, P=0.019). After adjustment for age, bilateral SV-sparing still remained a significant predictor for occurrence of PO. Conclusions We found that PO occurs significantly more often in patients undergoing bilateral SV-sparing RP when compared with age-matched comparison population