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. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

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. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health.

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 0.08 (95% CI 0.06-0.11) heritability and identified five loci associated with OSA (p<5.0×10-8): rs4837016 near GAPVD1 (GTPase activating protein and VPS9 domains 1), rs10928560 near CXCR4 (C-X-C motif chemokine receptor type 4), rs185932673 near CAMK1D (calcium/calmodulin-dependent protein kinase ID) and rs9937053 near FTO (fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 near RMST/NEDD1 (rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (rg=0.72 (95% CI 0.62-0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (rg>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.

Red Blood Cell Folate Insufficiency among nonpregnant Women of Childbearing age in Guatemala 2009 to 2010: Prevalence and predicted Neural Tube Defects risk.

BACKGROUND: The World Health Organization recently released recommendations stating that red blood cell (RBC) folate concentrations should be above 400 ng/L (906 nmol/L) for optimal prevention of folate-sensitive neural tube defects (NTDs). The objective of this study was to determine the distribution of folate insufficiency (FI) (<906 nmol/L) and potential risk of NTDs based on RBC folate concentrations among nonpregnant women of child-bearing age in Guatemala. METHODS: A national and regional multistage cluster probability survey was completed during 2009 to 2010 among Guatemalan women of child-bearing age 15 to 49 years of age. Demographic and health information and blood samples for RBC folate analyses were collected from 1473 women. Prevalence rate ratios of FI and predicted NTD prevalence were estimated based on RBC folate concentrations comparing subpopulations of interest. RESULTS: National FI prevalence was 47.2% [95% confidence interval, 43.3-51.1] and showed wide variation by region (18-81%). In all regions, FI prevalence was higher among indigenous (27-89%) than among nonindigenous populations (16-44%). National NTD risk based on RBC folate concentrations was estimated to be 14 per 10,000 live births (95% uncertainty interval, 11.1-18.6) and showed wide regional variation (from 11 NTDS in the Metropolitan region to 26 NTDs per 10,000 live births in the Norte region). CONCLUSION: FI remains a common problem in populations with limited access to fortified products, specifically rural, low income, and indigenous populations. However, among subpopulations that are most likely to have fortified food, the prevalence of FI is similar to countries with well-established fortification programs. Birth Defects Research (Part A) 106:587-595, 2016. © 2016 Wiley Periodicals, Inc.

Folate and Vitamin B12 Deficiency Among Non-pregnant Women of Childbearing-Age in Guatemala 2009-2010: Prevalence and Identification of Vulnerable Populations.

INTRODUCTION: Information on folate and vitamin B12 deficiency rates in Guatemala is essential to evaluate the current fortification program. The objectives of this study were to describe the prevalence of folate and vitamin B12 deficiencies among women of childbearing age (WCBA) in Guatemala and to identify vulnerable populations at greater risk for nutrient deficiency. METHODS: A multistage cluster probability study was designed with national and regional representation of nonpregnant WCBA (15-49 years of age). Primary data collection was carried out in 2009-2010. Demographic and health information was collected through face-to-face interviews. Blood samples were collected from 1473 WCBA for serum and red blood cell (RBC) folate and serum vitamin B12. Biochemical concentrations were normalized using geometric means. Prevalence rate ratios were estimated to assess relative differences among different socioeconomic and cultural groups including ethnicity, age, education level, wealth index and rural versus urban locality. RESULTS: National prevalence estimates for deficient serum [<10 nmol per liter (nmol/L)] and RBC folate (<340 nmol/L) concentrations were 5.1 % (95 % CI 3.8, 6.4) and 8.9 % (95 % CI 6.7, 11.7), respectively; for vitamin B12 deficiency (<148 pmol/L) 18.5 % (95 % CI 15.6, 21.3). Serum and RBC folate deficiency prevalences were higher for rural areas than for urban areas (8.0 vs. 2.0 % and 13.5 vs. 3.9 %, respectively). The prevalence of RBC folate deficiency showed wide variation by geographic region (3.2-24.9 %) and by wealth index (4.1-15.1 %). The prevalence of vitamin B12 deficiency also varied among regions (12.3-26.1 %). CONCLUSIONS: In Guatemala, folate deficiency was more prevalent among indigenous rural and urban poor populations. Vitamin B12 deficiency was widespread among WCBA. Our results suggest the ongoing need to monitor existing fortification programs, in particular regarding its reach to vulnerable populations.

Preconception health assessment in China, Lebanon and the Philippines: applicability to other countries.

To test the utility of a preconception checklist tool in identifying preconception health needs of women in three countries; China, Lebanon and the Philippines. An academic medical center within each country participated in the development and testing of a preconception checklist tool, which was administered over a 6 month period to selected target groups in each country. The checklist provided valuable data on the preconception health of 6,530 women. Aggregated data identified common preconception health needs across all countries, including provision of modern contraceptives and adequate immunization coverage; HIV and STI screening; treatment for anemia; and counseling for maintenance of a healthy weight. A preconception checklist tool was found to be useful in distinct cultural settings. The study was a pilot. Future steps include validation and standardization of the checklist, data from which could be used to help shape preconception care policies and implementation strategies.

Towards global model generalizability: independent cross-site feature evaluation for patient-level risk prediction models using the OHDSI network.

BACKGROUND: Predictive models show promise in healthcare, but their successful deployment is challenging due to limited generalizability. Current external validation often focuses on model performance with restricted feature use from the original training data, lacking insights into their suitability at external sites. Our study introduces an innovative methodology for evaluating features during both the development phase and the validation, focusing on creating and validating predictive models for post-surgery patient outcomes with improved generalizability. METHODS: Electronic health records (EHRs) from 4 countries (United States, United Kingdom, Finland, and Korea) were mapped to the OMOP Common Data Model (CDM), 2008-2019. Machine learning (ML) models were developed to predict post-surgery prolonged opioid use (POU) risks using data collected 6 months before surgery. Both local and cross-site feature selection methods were applied in the development and external validation datasets. Models were developed using Observational Health Data Sciences and Informatics (OHDSI) tools and validated on separate patient cohorts. RESULTS: Model development included 41 929 patients, 14.6% with POU. The external validation included 31 932 (UK), 23 100 (US), 7295 (Korea), and 3934 (Finland) patients with POU of 44.2%, 22.0%, 15.8%, and 21.8%, respectively. The top-performing model, Lasso logistic regression, achieved an area under the receiver operating characteristic curve (AUROC) of 0.75 during local validation and 0.69 (SD = 0.02) (averaged) in external validation. Models trained with cross-site feature selection significantly outperformed those using only features from the development site through external validation (P < .05). CONCLUSIONS: Using EHRs across four countries mapped to the OMOP CDM, we developed generalizable predictive models for POU. Our approach demonstrates the significant impact of cross-site feature selection in improving model performance, underscoring the importance of incorporating diverse feature sets from various clinical settings to enhance the generalizability and utility of predictive healthcare models.

Distinct and shared genetic architectures of gestational diabetes mellitus and type 2 diabetes.

Gestational diabetes mellitus (GDM) is a common metabolic disorder affecting more than 16 million pregnancies annually worldwide1,2. GDM is related to an increased lifetime risk of type 2 diabetes (T2D)1-3, with over a third of women developing T2D within 15 years of their GDM diagnosis. The diseases are hypothesized to share a genetic predisposition1-7, but few studies have sought to uncover the genetic underpinnings of GDM. Most studies have evaluated the impact of T2D loci only8-10, and the three prior genome-wide association studies of GDM11-13 have identified only five loci, limiting the power to assess to what extent variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen study and identified 13 GDM-associated loci, including nine new loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into the following two distinct categories: one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis and placental expression.

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- 8), more than half of which have not previously been documented in thyroid disease. In 48 of these, a protein-coding variant is the lead SNP or is highly correlated (r2 > 0.95) with the lead SNP at the locus, including low-frequency coding variants at LAG3, ZAP70, TG, TNFSF11, IRF3, S1PR4, HABP2, ZNF429 as well as established variants at ADCY7, IFIH1 and TYK2. The variants at LAG3 (P67T), ZAP70 (T155M), and TG (Q655X) are highly enriched in Finland and functional experiments in T-cells demonstrate that the ZAP70:T155M allele reduces T-cell activation. By employing a large-scale scan of non-thyroid autoimmunity and a published meta-analysis of TSH levels, we use a Bayesian classifier to dissect the associated loci into distinct groupings and from this estimate, a significant proportion are involved in systemic (i.e., general to multiple autoimmune conditions) autoimmunity (34%) and another subset in thyroid-specific dysfunction (17%). By comparing these association results further to other common disease endpoints, we identify a noteworthy overlap with skin cancer, with 10% of AIHT loci showing a consistent but opposite pattern of association where alleles that increase the risk of hypothyroidism have protective effects for skin cancer. The association results, including genes encoding checkpoint inhibitors and other genes affecting protein levels of PD1, bolster the causal role of natural variation in autoimmunity influencing cancer outcomes.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

LAVAA: a lightweight association viewer across ailments.

Motivation: Biobank scale genetic associations results over thousands of traits can be difficult to visualize and navigate. Results: We have created LAVAA, a visualization web-application to generate genetic volcano plots for simultaneously considering the P-value, effect size, case counts, trait class and fine-mapping posterior probability at a single-nucleotide polymorphism (SNP) across a range of traits from a large set of genome-wide association study. We find that user interaction with association results in LAVAA can enrich and enhance the biological interpretation of individual loci. Availability and implementation: LAVAA is available as a stand-alone web service (https://geneviz.aalto.fi/LAVAA/) and will be available in future releases of the finngen.fi website starting with release 10 in late 2023.

Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4.

Background: Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database. Methods: Clinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database. Results: A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7). Conclusions: Here, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism.

An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease.

Multivariate methods are known to increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. They have, however, lacked essential analytic tools to follow-up and understand the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate regression coefficients which are lacking from multivariate results. Our method overcomes this problem by using Canonical Correlation Analysis to turn each multivariate association into its optimal univariate Linear Combination Phenotype (LCP). This enables an LCP-GWAS, which in turn generates the statistics required for follow-up analyses. We implemented our method on 12 highly correlated inflammatory biomarkers in a Finnish population-based study. Altogether, we identified 11 associations, four of which (F5, ABO, C1orf140 and PDGFRB) were not detected by biomarker-specific analyses. Fine-mapping identified 19 signals within the 11 loci and driver trait analysis determined the traits contributing to the associations. A phenome-wide association study on the 19 representative variants from the signals in 176,899 individuals from the FinnGen study revealed 53 disease associations (p < 1 × 10-4). Several reported pQTLs in the 11 loci provided orthogonal evidence for the biologically relevant functions of the representative variants. Our novel multivariate analysis workflow provides a powerful addition to standard univariate GWAS analyses by enabling multivariate GWAS follow-up and thus promoting the advancement of powerful multivariate methods in genomics.

Phenome-wide association studies across large population cohorts support drug target validation.

Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.

An international surgical exchange program for children with cleft lip/cleft palate in Manaus, Brazil: patient and family expectations of outcome.

Increasingly, surgeons are traveling from the developed to the developing world to volunteer their services. They can often make an enormous difference in the lives of patients they serve, but they must understand that these patients exist in a sociocultural matrix in which the meaning of the condition they have and the future they face are determined by a host of factors over and above the specific surgery itself. This means that programs in which teams quickly go in and out of a country must take into account and plan for longer term follow-up by colleagues within that country as well as develop and target rehabilitation services and educational messages to ensure maximum benefits from the intervention performed. This study examines the long-term implications of a short-term surgical team intervention for pediatric patients with cleft lip/cleft palate and their families in the Amazon region of Brazil.