A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic risk.

Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases.

Whole-genome sequencing identifies variants in ANK1, LRRN1, HAS1, and other genes and regulatory regions for stroke in type 1 diabetes.

Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters.

Adolescent leisure-time physical activity and eating disorders: a longitudinal population-based twin study.

Purpose: High levels of physical activity have been documented in eating disorder patients. Our aim was to examine whether adolescent leisure-time physical activity is prospectively associated with eating disorders in adolescence and young adulthood.

Methods: Finnish twins born in 1983-1987 reported their physical activity frequency at ages 12, 14, and 17.

MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease.

Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk.

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.

How the oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients.

X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes.

Background: Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines.

A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells.

Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death.

Serum hydroxysteroid (17beta) dehydrogenase 1 concentration in pregnant women correlates with pregnancy-associated plasma protein A but does not serve as an independent marker for preeclampsia†.

Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is a steroid synthetic enzyme expressed in ovarian granulosa cells and placental syncytiotrophoblasts. Here, HSD17B1 serum concentration was measured with a validated immunoassay during pregnancy at three time points (12-14, 18-20 and 26-28 weeks of gestation). The concentration increased 2.

Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer.

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group.

Generation and characterisation of scalable and stable human pluripotent stem cell-derived microvascular-like endothelial cells for cardiac applications.

Coronary microvascular disease (CMD) and its progression towards major adverse coronary events pose a significant health challenge. Accurate in vitro investigation of CMD requires a robust cell model that faithfully represents the cells within the cardiac microvasculature. Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) offer great potential; however, they are traditionally derived via differentiation protocols that are not readily scalable and are not specified towards the microvasculature.

Genetic Liability to Cardiovascular Disease, Physical Activity, and Mortality: Findings from the Finnish Twin Cohort.

Purpose: We investigated whether longitudinally assessed physical activity (PA) and adherence specifically to World Health Organization PA guidelines mitigate or moderate mortality risk regardless of genetic liability to cardiovascular disease (CVD). We also estimated the causality of the PA-mortality association.

Methods: The study used the older Finnish Twin Cohort with 4897 participants aged 33 to 60 yr (54.

Rare genetic variation in VE-PTP is associated with central serous chorioretinopathy, venous dysfunction and glaucoma.

Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen.

Association of obesity to reaction time and visual memory in schizophrenia.

Background: Both overweight and cognitive deficits are common among people with schizophrenia (SZ) and schizoaffective disorder. The results in earlier studies have been inconsistent on whether overweight is associated with cognitive deficits in psychotic disorders.

Aims: Our aim in this study was to detect possible associations between obesity and cognitive deficits among study participants with SZ and schizoaffective disorder.

Risk assessment of hypertensive disorders of pregnancy and other adverse pregnancy outcomes after frozen embryo transfers following an artificial cycle: A retrospective cohort study.

Objectives: The primary aim was to investigate if frozen embryo transfer (FET) without a corpus luteum increases the risk of hypertensive disorders of pregnancy (HDP). The secondary aim was to investigate other adverse maternal and perinatal outcomes.

Methods: This was a retrospective cohort study of 1168 singleton pregnancies and live births following a FET with either an artificial cycle (AC-FET) (n = 631) or a natural/modified natural/stimulated cycle (CL-FET) (n = 537) between 2012 and 2020.

Associations of plant-based foods, red and processed meat, and dairy with gut microbiome in Finnish adults.

Purpose: Population-based studies on the associations of plant-based foods, red meat or dairy with gut microbiome are scarce. We examined whether the consumption of plant-based foods (vegetables, potatoes, fruits, cereals), red and processed meat (RPM) or dairy (fermented milk, cheese, other dairy products) are related to gut microbiome in Finnish adults.

Methods: We utilized data from the National FINRISK/FINDIET 2002 Study (n = 1273, aged 25-64 years, 55% women).

A harmonized public resource of deeply sequenced diverse human genomes.

Underrepresented populations are often excluded from genomic studies owing in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high-quality set of 4094 whole genomes from 80 populations in the HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs.

Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is a common cancer with a five-year survival rate around 60%, indicating a need for new treatments. BH3 mimetics are small molecules that inhibit anti-apoptotic Bcl-2 family proteins, resulting in apoptosis induction.

Methods: We performed a high-throughput screen using a Myogel matrix to identify the synergy between irradiation and the novel BH3 mimetics A-1155463, A-1331852, and navitoclax in 12 HNSCC cell lines, normal (NOF) and cancer-associated fibroblasts (CAF), and dysplastic keratinocytes (ODA).