Fine-Scale Genetic Structure in Finland

Coupling dense genotype data with new computational methods offers unprecedented opportunities for individual-level ancestry estimation once geographically precisely defined reference data sets become available. We study such a reference data set for Finland containing 2376 such individuals from the FINRISK Study survey of 1997 both of whose parents were born close to each other. This sampling strategy focuses on the population structure present in Finland before the 1950s. By using the recent haplotype-based methods ChromoPainter (CP) and FineSTRUCTURE (FS) we reveal a highly geographically clustered genetic structure in Finland and report its connections to the settlement history as well as to the current dialectal regions of the Finnish language. The main genetic division within Finland shows striking concordance with the 1323 borderline of the treaty of Noteborg. In general, we detect genetic substructure throughout the country, which reflects stronger regional genetic differences in Finland compared to, for example, the UK, which in a similar analysis was dominated by a single unstructured population. We expect that similar population genetic reference data sets will become available for many more populations in the near future with important applications, for example, in forensic genetics and in genetic association studies. With this in mind, we report those extensions of the CP + FS approach that we found most useful in our analyses of the Finnish data.Peer reviewe

Geographic Variation and Bias in the Polygenic Scores of Complex Diseases and Traits in Finland

Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.Peer reviewe

Lack of cardiac and high-fat diet induced metabolic phenotypes in two independent strains of Vegf-b knockout mice

Peer reviewe

Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy

Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.Research supported by FAPESP (2010/11005-5 and 2010/04462) and CNPq (#471939/2010-2 and 483005/2012-6

Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mumol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans

Genome-wide risk prediction of common diseases across ancestries in one million people

Peer reviewe

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Is catchment geodiversity a useful surrogate of aquatic plant species richness?

Aim Conserving freshwater biodiversity in a rapidly changing world requires updated planning schemes and research efforts. Geodiversity – the diversity of Earth surface forms, materials and processes – and biodiversity are interlinked at a fundamental level. This relationship is being considered in a growing number of studies, yet research from freshwater environments is scarce. We used geodiversity (rock-type, soil-type and geomorphological richness), local and climatic variables to explore whether geodiversity can be used as a surrogate for aquatic plant species richness in lakes and rivers. Location Finland. Taxon Aquatic plants. Methods We compared geodiversity variables (measured within 1-km2 grid cells) to well-studied local (e.g. area, alkalinity) and climate (e.g. growing degree-days) variables, and examined the patterns between habitat types (lakes and rivers) and among all taxa and major functional groups (helophytes and hydrophytes). We modelled lake (n = 145) and river (n = 146) plant species richness with generalized linear models, and further partitioned variation to measure the independent and shared contributions of the geodiversity, climate and local environmental variable groups. As a complementary analysis, and to identify single important variables explaining variation in aquatic plant species richness, we utilized boosted regression trees. Results We found a positive relationship between aquatic plant species richness and catchment geodiversity variation with recurring patterns across two different freshwater habitat types and two aquatic plant functional groups. Higher variation in geodiversity (measured at landscape scale) supported higher freshwater biodiversity (measured at the local scale) of lakes and rivers. Main conclusions Geodiversity can be a useful addition to biodiversity modelling, and it should be considered in conservation schemes and monitoring efforts, further supporting the principle of conserving nature's stage. Yet, differences between habitats and functional groups suggest that more habitat-specific approaches and multiple biodiversity measures should be considered. Our study is an important signpost guiding further studies on the biodiversity–geodiversity relationship in freshwater ecosystems