Rate of de novo mutations and the importance of father's age to disease risk.

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.

GORpipe: a query tool for working with sequence data based on a Genomic Ordered Relational (GOR) architecture.

MOTIVATION: Our aim was to create a general-purpose relational data format and analysis tools to provide an efficient and coherent framework for working with large volumes of DNA sequence data. RESULTS: For this purpose we developed the GORpipe software system. It is based on a genomic ordered architecture and uses a declarative query language that combines features from SQL and shell pipe syntax in a novel manner. The system can for instance be used to annotate sequence variants, find genomic spatial overlap between various types of genomic features, filter and aggregate them in various ways. AVAILABILITY AND IMPLEMENTATION: The GORpipe software is freely available for non-commercial academic usage and can be downloaded from www.nextcode.com/gorpipe CONTACT: hakon@wuxinextcode.comSupplementary information: Supplementary data are available at Bioinformatics online.

A simple and objective marker for stress.

OBJECTIVE: To examine the association between pressure pain sensitivity (PPS) at sternum and various well established physiological stress measures among opera singers during a performance as a measure for transitional stress, and resting values in out-clinic patients as a measure for persistent stress. METHODS: Changes in PPS on the index finger and sternum, middle blood pressure (MAP), heart rate (HR), pressure-rate-product (PRP) and salivary cortisol (SCO) were recorded in 26 opera solo singers during a performance. Resting PPS, HR, MAP, PRP and presence of a noxious withdrawal reflex (NWR) were recorded in 181 out-clinic patients. RESULTS: During opera performance, the PPS on sternum changed concomitantly with MAP (correlation coefficient (r) r=0.42, p<0.005), HR (r=0.55, p<0.001), PRP (r=0.54, p<0.001) and SCO (r=0.26, p=0.066). During rest, a significant correlation was found between PPS on sternum and HR, PRP and presence of noxious withdrawal reflex (all p<0.01). CONCLUSIONS: The PPS measurement at sternum was associated with well established physiological stress measures and may represent a simple, objective and reliable measure of physiological stress used by both non-professional and professionals.

Sequence variants from whole genome sequencing a large group of Icelanders.

We have accumulated considerable data on the genetic makeup of the Icelandic population by sequencing the whole genomes of 2,636 Icelanders to depth of at least 10X and by chip genotyping 101,584 more. The sequencing was done with Illumina technology. The median sequencing depth was 20X and 909 individuals were sequenced to a depth of at least 30X. We found 20 million single nucleotide polymorphisms (SNPs) and 1.5 million insertions/deletions (indels) that passed stringent quality control. Almost all the common SNPs (derived allele frequency (DAF) over 2%) that we identified in Iceland have been observed by either dbSNP (build 137) or the Exome Sequencing Project (ESP) while only 60 and 20% of rare (DAF<0.5%) SNPs and indels in coding regions, the most heavily studied parts of the genome, have been observed in the public databases. Features of our variant data, such as the transition/transversion ratio and the length distribution of indels, are similar to published reports.

Large-scale whole-genome sequencing of the Icelandic population.

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

Identification of low-frequency variants associated with gout and serum uric acid levels.

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.

Long-term effects of integrated rehabilitation in patients with stroke: a nonrandomized comparative feasibility study.

BACKGROUND AND PURPOSE: Integrated rehabilitation (IR) in patients with stroke with respect to death rate and feasibility, initiated as a reduced death rate, was observed in patients with angina pectoris receiving IR. DESIGN: A case-control study included 73 consecutive patients with ischemic stroke. Death rates were compared with those of the general Danish population matched for age, gender, and observation period, as well as data from the community-based Copenhagen Stroke Study. INTERVENTIONS: IR was conducted in an outpatient clinic, by professionals as well as by the patient: the former as a specific acupuncture treatment, the latter as a comprehensive biofeedback guided stress management program including diets, physical- and relaxation exercise, Chinese health philosophy, cognitive and mindfulness-related exercises, and specific biofeedback guided acupressure. RESULTS: The 4(1/2)-year accumulated risk of death was 11.6% (95 confidence limits: 3.2%-20.0%) for the 73 patients with stroke treated with IR, compared to 18.4% for the general Danish population matched for sex, age, and time period. The corresponding figures for patients receiving conventional stroke treatment were 43.2% (95 confidence limits: 39.7%- 46.7%), and 20.0% for the general Danish population matched for sex, age, and time period. CONCLUSIONS: IR was found to be feasible for patients with stroke as a complementary treatment to conventional stroke treatment, and added no risk of dying when compared to Danish stroke patients receiving conventional medical treatment. The results invite further testing in a randomized trial.