Socio-demographic and genetic risk factors for drug adherence and persistence across 5 common medication classes.

Low drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1,814,591 individuals from Finnish nationwide registries, 217,005 with genetic data from Finland and Estonia). Need for social assistance and immigration status show a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.

Autoimmune hypothyroidism GWAS reveals independent autoimmune and thyroid-specific contributions and an inverse relation with cancer risk.

The high prevalence of autoimmune hypothyroidism (AIHT) - more than 5% in human populations - provides a unique opportunity to unlock the most complete picture to date of genetic loci that underlie systemic and organ-specific autoimmunity. Using a meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, we dissect associations along axes of thyroid dysfunction and autoimmunity. This largest-to-date scan of hypothyroidism identifies 418 independent associations (p < 5×10), more than half of which have not previously been documented in thyroid disease.

Genetic Analysis of Obstructive Sleep Apnea and Its Relationship with Severe COVID-19.

Although patients with obstructive sleep apnea (OSA) have a higher risk for coronavirus disease (COVID-19) hospitalization, the causal relationship has remained unexplored. To understand the causal relationship between OSA and COVID-19 by leveraging data from vaccination and electronic health records, genetic risk factors from genome-wide association studies, and Mendelian randomization. We elucidated genetic risk factors for OSA using FinnGen (total  = 377,277), performing genome-wide association.

Integration of Biomarker Polygenic Risk Score Improves Prediction of Coronary Heart Disease.

There are several established biomarkers for coronary heart disease (CHD), including blood pressure, cholesterol, and lipoproteins. It is of high interest to determine how a combined polygenic risk score (PRS) of CHD-associated biomarkers (BioPRS) can further improve genetic prediction of CHD. We developed CHDBioPRS, combining BioPRS with PRS of CHD in the UK Biobank and tested it on FinnGen.

Evidence from Finland and Sweden on the relationship between early-life diseases and lifetime childlessness in men and women.

The percentage of people without children over their lifetime is approximately 25% in men and 20% in women. Individual diseases have been linked to childlessness, mostly in women, yet we lack a comprehensive picture of the effect of early-life diseases on lifetime childlessness. We examined all individuals born in 1956-1968 (men) and 1956-1973 (women) in Finland (n = 1,035,928) and Sweden (n = 1,509,092) to the completion of their reproductive lifespan in 2018.

Genetics of sleep medication purchases suggests causality from sleep problems to psychiatric traits.

Study Objectives: Over 10% of the population in Europe and in the United States use sleep medication to manage sleep problems. Our objective was to elucidate genetic risk factors and clinical correlates that contribute to sleep medication purchase and estimate the comorbid impact of sleep problems.

Methods: We performed epidemiological analysis for psychiatric diagnoses, and genetic association studies of sleep medication purchase in 797 714 individuals from FinnGen Release 7 (N = 311 892) and from the UK Biobank (N = 485 822).

Use of electronic health record data mining for heart failure subtyping.

Objective: To assess whether electronic health record (EHR) data text mining can be used to improve register-based heart failure (HF) subtyping. EHR data of 43,405 individuals from two Finnish hospital biobanks were mined for unstructured text mentions of ejection fraction (EF) and validated against clinical assessment in two sets of 100 randomly selected individuals. Structured laboratory data was then incorporated for a categorization by HF subtype (HF with mildly reduced EF, HFmrEF; HF with preserved EF, HFpEF; HF with reduced EF, HFrEF; and no HF).

Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration.

Importance: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases.

FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants.

Genetic predictors of lifelong medication-use patterns in cardiometabolic diseases.

Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P < 5 × 10) associated with medication use.

Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation.

Inflammatory and infectious upper respiratory diseases (ICD-10: J30-J39), such as diseases of the sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyze genome-wide association to eight upper respiratory diseases (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. Aiming to understand which genetic loci contribute to susceptibility to upper respiratory diseases in general and its subtypes, we detect 41 independent genome-wide significant loci, distinguishing impact on sinonasal or pharyngeal diseases, or both.

Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure.

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history.

Genetic risk factors have a substantial impact on healthy life years.

The impact of genetic variation on overall disease burden has not been comprehensively evaluated. We introduce an approach to estimate the effect of genetic risk factors on disability-adjusted life years (DALYs; 'lost healthy life years'). We use genetic information from 735,748 individuals and consider 80 diseases.

Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging.

Length and quality of life are important to us all, yet identification of promising drug targets for human aging using genetics has had limited success. In the present study, we combine six European-ancestry genome-wide association studies of human aging traits-healthspan, father and mother lifespan, exceptional longevity, frailty index and self-rated health-in a principal component framework that maximizes their shared genetic architecture. The first principal component (aging-GIP1) captures both length of life and indices of mental and physical wellbeing.

Clinical Conditions and Their Impact on Utility of Genetic Scores for Prediction of Acute Coronary Syndrome.

Background: Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease. Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions.

Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population.

Importance: The c.1102C>T, p.(Gln368Ter) variant in the myocilin (MYOC) gene is a known risk allele for glaucoma.

ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease.

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435).

Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

[This corrects the article DOI: 10.1371/journal.pgen.

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.

Genetics of 35 blood and urine biomarkers in the UK Biobank.

Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.