Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.Peer reviewe

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66-0.89]) and lower household income (OR = 0.77 [0.66-0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38-0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32-0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26-0.37]), lower-income (OR = 0.66 [0.57-0.77]), lower subjective health (OR = 0.72 [0.61-0.83]), and increased mortality (Cox's HR = 1.55 [1.21-1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.Peer reviewe

The Nordic back pain subpopulation program: predicting outcome among chiropractic patients in Finland

<p>Abstract</p> <p>Background</p> <p>In a previous Swedish study it was shown that it is possible to predict which chiropractic patients with persistent LBP will not report definite improvement early in the course of treatment, namely those with LBP for altogether at least 30 days in the past year, who had leg pain, and who did not report definite general improvement by the second treatment. The objectives of this study were to investigate if the predictive value of this set of variables could be reproduced among chiropractic patients in Finland, and if the model could be improved by adding some new potential predictor variables.</p> <p>Methods</p> <p>The study was a multi-centre prospective outcome study with internal control groups, carried out in private chiropractic practices in Finland. Chiropractors collected data at the 1st, 2^ndand 4^thvisits using standardized questionnaires on new patients with LBP and/or radiating leg pain. Status at base-line was identified in relation to pain and disability, at the 2^ndvisit in relation to disability, and "definitely better" at the 4^thvisit in relation to a global assessment. The Swedish questionnaire was used including three new questions on general health, pain in other parts of the spine, and body mass index.</p> <p>Results</p> <p>The Swedish model was reproduced in this study sample. An alternative model including leg pain (yes/no), improvement at 2^ndvisit (yes/no) and BMI (underweight/normal/overweight or obese) was also identified with similar predictive values. Common throughout the testing of various models was that improvement at the 2^ndvisit had an odds ratio of approximately 5. Additional analyses revealed a dose-response in that 84% of those patients who fulfilled none of these (bad) criteria were classified as "definitely better" at the 4^thvisit, vs. 75%, 60% and 34% of those who fulfilled 1, 2 or all 3 of the criteria, respectively.</p> <p>Conclusion</p> <p>When treating patients with LBP, at the first visits, the treatment strategy should be different for overweight/obese patients with leg pain as it should be for all patients who fail to improve by the 2^ndvisit. The number of predictors is also important.</p

The Indo-European flyway: Opportunities and constraints reflected by Common Rosefinches breeding across Europe

Aim The configuration of the earth's landmasses influences global weather systems and spatiotemporal resource availability, thereby shaping biogeographical patterns and migratory routes of animals. Here, we aim to identify potential migratory barriers and corridors, as well as general migration strategies within the understudied Indo-European flyway.Location Europe, Central Asia.Major taxon studied Common rosefinches.Methods We used a combination of theoretical optimization modelling and empirical tracking of Common Rosefinches (Carpodacus erythrinus) breeding across a large latitudinal gradient in Europe. First, we identified optimal migration routes driven by wind and resource availability along the Indo-European flyway. Second, we tracked rosefinches from five breeding populations using light-level geolocators. Finally, we compared to what extent empirical tracks overlapped with the modelled optimal routes.ResultsIn autumn, theoretical wind driven migration routes formed a broad-front corridor connecting Europe and the Indian Subcontinent while the theoretical resource driven routes formed a distinct north-south divide. The latter pattern also reflected the rosefinch tracks with all but the most southerly breeding birds making a northern detour towards non-breeding sites in Pakistan and India. In spring, the resource availability model predicted a similar migratory divide, however, the southern route seemed relatively more favourable and closely matched with the optimal wind driven migration routes. Spring tracking data showed larger overlap with the modelled wind driven migration routes compared to the resource driven routes.Main conclusionsOptimal wind and resource driven migration routes along the Indo-European flyway are seasonally specific and to a large extend do not overlap with one another. Under these conditions, migratory birds adopt seasonally distinct migration strategies following energy minimization strategy in autumn, driven by resource availability, and time minimizing strategy in spring, driven by wind conditions. Our optimal migration models can be applied worldwide and used to validate against empirical data to explain large-scale biogeographic pattern of migratory animals.</p

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Power balance control and dimensioning of a hybrid off-grid energy system for a Nordic climate townhouse

This paper investigates conversion of a Nordic oil-heated townhouse into carbon-neutral by different energy efficiency (EE) improvements and an off-grid system including solar photovoltaics (PV), wind power, and battery and hydrogen energy storage systems (BESS and HESS). A heat-pump-based heating system including waste heat recovery (WHR) from the HESS and an off-grid electrical system are dimensioned for the building by applying models developed in MATLAB and Microsoft Excel to study the life cycle costs (LCC). The work uses a measured electrical load profile, and the heat generation of the new heating system and the power generation are simulated by commercial software. It is shown that the EE improvements and WHR from the HESS have a positive effect on the dimensioning of the off-grid system, and the LCC can be reduced by up to €2 million. With the EE improvements and WHR, the component dimensioning can be reduced by 22%–41% and 13%–51% on average, respectively. WHR can cover up to 57% of the building's annual heat demand, and full-power dimensioning of the heat pump is not reasonable when WHR is applied. Wind power was found to be very relevant in the Nordic conditions, reducing the LCC by 32%.</p