A nationwide registry-based observational study of thyroid disease incidence in the Faroe Islands.

OBJECTIVE: The occurrence of thyroid disease varies among populations. While the iodine nutrition level of the Faroese seems to have been decreasing over the past decades, there is no systematic evaluation of the thyroid disease pattern in the Faroe Islands. Such knowledge of thyroid disease occurrence in the North Atlantic region may support healthcare planning and prevention. To investigate incidence rates, including subtypes of thyroid diseases, and demographic characteristics of thyroid disease patients in the Faroe Islands, to improve understanding of the patterns and trends of these disorders. DESIGN AND METHOD: A registry-based observational study was conducted over 10 years, encompassing all adult Faroese individuals. PATIENTS AND MEASUREMENTS: Health records from general practitioners and hospitals were used to identify incident cases of thyroid diseases. Validation was performed using multiple data sources. The incidence rates were standardised using population data from the middle of the study period 2006-2018. RESULTS: Among the 1152 individuals diagnosed with thyroid disease, the standardised incidence rates per 100,000 person-years were 55 for hyperthyroidism and 112 for hypothyroidism, and around four times higher in women than in men. Hashimoto's thyroiditis was the dominant cause of hypothyroidism, while Graves' disease was the leading cause of hyperthyroidism. The incidence of hypothyroidism increases with age. A decreasing trend was observed over time for both hypothyroidism and hyperthyroidism. CONCLUSION: Considering the decrease in iodine nutrition levels over the past decades, we were surprised by the high incidence of autoimmune thyroid disease. The findings highlight the need for continuous monitoring of thyroid disease occurrence in coastal areas of the North Atlantic Ocean.

Childhood cancer incidence and survival in the Faroe Islands, 1960 to 2019.

BACKGROUND AND PURPOSE: This study is the first report regarding childhood cancer in the Faroe Islands and describes the incidence and survival of childhood cancer over the last 60 years in the Faroe Islands. MATERIAL AND METHODS: We included all Faroese children registered with a cancer diagnosis up to the age of 19 years in the Faroese Cancer Registry from 1960 to 2019 and in the Danish Childhood Cancer Registry from 1985 to 2019 in this study. We report the number of incident cancers classified according to the 12 main diagnostic groups in the International Classification of Childhood Cancer, third edition (ICCC-3), but due to small numbers some groups have been combined in the results shown. We report age-standardized incidence rates (world standard population) (ASIR). We also show all-cause survival by incidence stratified by 20-year periods. RESULTS: There were 114 childhood cancers in the Faroe Islands from 1960 to 2019, corresponding to an ASIR of 13.0 per 100,000 person-years. The most common cancer groups in Faroese children were brain and spinal tumors, followed by leukemias and lymphomas. All-cause survival improved for children diagnosed over time, with a 5-year survival of 43.5% for those diagnosed from 1960 to 1979 and 85.6% for children diagnosed from 2000 to 2019. CONCLUSION: Childhood cancer in the Faroes was slightly rarer than in most other high-income countries. Brain and spinal tumors were the most common cancer group in Faroese children. Survival for Faroese children with cancer has improved substantially in the study period.

Cancer survival in the Faroe Islands over the last 50 years compared to the other Nordic countries.

As sustained development in cancer treatment protocols have led to improved survival in most areas of the world, surveillance is needed to ensure that small populations follow suit. Our study reports age-standardized relative cancer survival in the Faroe Islands compared to the other Nordic countries. We present 1- and 5-year survival estimates and corresponding 95% confidence intervals for the Faroe Islands and compare them with estimates for the Nordic countries. The data for this article has been obtained through the NORDCAN collaboration (2019 data). Age-standardized relative survival was estimated using shared R codes on individual-level data within each country. Ten-year calendar inclusion periods were used in addition to the usual 5-year calendar periods to include cancer sites with few cases, which is especially beneficial to the smaller populations. The primary findings were that 1- and 5-year survival were consistently lower in the Faroes for the summary group all sites but non-melanoma skin cancer for both women and men. Further, 5-year survival was lower for women with ovarian cancer and men with lung cancer than in other Nordic countries. Previously, breast cancer survival was low in the Faroes but has improved to a comparable level over the last few years. Colorectal cancer survival was relatively high for both sexes. The reported estimates in this article call for further research to investigate the cancers with lower survival and should call for actions to improve the survival of Faroese cancer patients.

Factors influencing the immune response over 15 months after SARS-CoV-2 infection: A longitudinal population-wide study in the Faroe Islands.

BACKGROUND: The durability of SARS-CoV-2 antibody response and the resulting immunity to COVID-19 is unclear. OBJECTIVES: To investigate long-term humoral immunity to SARS-CoV-2. METHODS: In this nationwide, longitudinal study, we determined antibody response in 411 patients aged 0-93 years from two waves of infections (March to December 2020) contributing 1063 blood samples. Each individual had blood drawn on 4-5 occasions 1-15 months after disease onset. We measured total anti-SARS-CoV-2 receptor-binding domain (RBD) antibody using a qualitative RBD sandwich ELISA, IgM, IgG and IgA levels using an quantitative in-house ELISA-based assay  and neutralizing antibodies (NAbs) using an in-house ELISA-based pseudoneutralizing assay. IgG subclasses were analyzed in a subset of samples by ELISA-based assay. We used nonlinear models to study the durability of SARS-CoV-2 antibody responses and its influence over time. RESULTS: After 15 months, 94% still had detectable circulating antibodies, mainly the IgG isotype, and 92% had detectable NAbs. The distribution of IgG antibodies varied significantly over time, characterized by a biphasic pattern with an initial decline followed by a plateau after approximately 7 months. However, the NAbs remained relatively stable throughout the period. The strength of the antibody response was influenced by smoking and hospitalization, with lower IgG levels in smokers and higher levels in hospitalized individuals. Antibody stability over time was mainly associated with male sex and older age with higher initial levels but more marked decrease. CONCLUSIONS: The humoral immune response to SARS-CoV-2 infection varies depending on behavioral factors and disease severity, and antibody stability over 15 months was associated with sex and age.

FarGen: Elucidating the distribution of coding variants in the isolated population of the Faroe Islands.

Here we present results from FarGen Phase I exomes. This dataset is based on the FarGen cohort, which consists of 1,541 individuals from the isolated population of the Faroe Islands. The purpose of this cohort is to serve as a reference catalog of coding variants, and to conduct population genetic studies to better understand the genetic contribution to various diseases in the Faroese population. The first whole-exome data set comprise 465 individuals and a total of 148,267 genetic variants were discovered. Principle Component Analysis indicates that the population is isolated and weakly structured. The distribution of variants in various functional classes was compared with populations in the gnomAD dataset; the results indicated that the proportions were consistent across the cohorts, but probably due to a small sample size, the FarGen dataset contained relatively few rare variants. We identified 19 variants that are classified as pathogenic or likely pathogenic in ClinVar; several of these variants are associated with monogenetic diseases with increased prevalence in the Faroe Islands. The results support previous studies, which indicate that the Faroe Islands is an isolated and weakly structured population. Future studies may elucidate the significance of the 19 pathogenic variants that were identified. The FarGen Phase I dataset is an important step for genetic research in the Faroese population, and the next phase of FarGen will increase the sample size and broaden the scope.

Effects of Postdischarge High-Protein Oral Nutritional Supplements and Resistance Training in Malnourished Surgical Patients: A Pilot Randomized Controlled Trial.

The presence of malnutrition is increasingly becoming a postdischarge problem in surgical patients. We aimed to investigate whether oral nutritional supplements combined with resistance training could minimize skeletal muscle atrophy in surgical patients after discharge. This randomized controlled study was conducted at the Department of Surgery, National Hospital of Faroe Islands from 2018 to 2020. A total of 45 patients aged 37−74 years participated and were allocated to one of three groups: diet (DI; n = 13), exercise and diet (EX + DI; n = 16), or control (CON; n = 16). The intervention period lasted 8 weeks. The intervention groups received individual dietary counselling and a protein-rich oral nutritional supplement twice a day containing 22 g of protein/day. Patients in the EX + DI group were assigned to resistance training sessions. Patients in the CON group received standard care. The primary outcome was change in lean body mass (LBM). Secondary outcomes were change in body weight, handgrip strength, quality of life, surgery-related side effects, energy and protein intake, length of stay and one-year mortality. To estimate within-group changes, linear mixed models including group−time interactions as fixed effects and patients as random effects were fitted. Within-group change in LBM was 233, 813 and 78 g in the DI, EX + DI and CON groups, respectively, with no significant between-group difference (p > 0.05). Pain score declined more (p = 0.04) in the EX + DI group compared with the CON group. Body weight, handgrip strength, quality of life and surgery-related side effects did not differ between groups. At the end of study, mean cumulative weight change in the DI and EX + DI groups was 0.4% and 1.6%, respectively, whereas the CON group experienced a weight loss of −0.6%. No significant difference in primary outcome between groups was noted. However, our results indicate some benefits from exercise and nutrition for malnourished surgical patients.

Cancer in the Faroe Islands from 1960-2019 - incidence, mortality, and comparisons with the other Nordic countries.

Purpose: In this paper, we present age-standardized cancer incidence and mortality rates in the Faroe Islands. We also compare with the Nordic rates and show incidence rate ratios (IRR) and mortality rate ratios (MRR).Materials and methods: The Faroese cancer registry (FCR) was established in 1994, with incidence available from 1960 and mortality from 1983. The FCR is a part of the NORDCAN collaboration, where the different Nordic countries all report anonymized cancer data by standardized methods, ensuring comparability. Validation efforts revealed that 13% of cases had not been reported to the FCR from 2006 to 2019, emphasizing the need for continued validation efforts of cancer registries. After validation, we submitted the updated cancer cases to NORDCAN and now present this data, taken directly from the NORDCAN website (2019 data).Results: We found that the incidence of the summary group all cancers in the Faroe Islands increased from 1960 to 2019, while cancer mortality decreased from 1983 to 2019. Comparisons with Nordic rates showed significantly lower IRRs for cancer in all cancers, bladder and urinary tract, and skin cancer for both sexes, while IRR was lower for breast cancer in women and prostate cancer in men. Contrary, IRR was higher for rectum and kidney cancer in women and esophagus and testicular cancer in men. There was an increased MRR for cancer in female organs, bladder and urinary tract, and kidney cancer in women, and esophagus and pancreas cancer in men. In contrast, malignant hematopoietic diseases and melanoma in women had a lower MRR.Conclusions: Cancer incidence in the Faroe Islands was lower than in the other Nordic countries. Of particular interest, the incidence of testicular cancer saw a steep increase during the last 20 years, and an investigation into possible causes for this is needed.

Meiotic drive in chronic lymphocytic leukemia compared with other malignant blood disorders.

The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. "healthy and unaffected", due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve¼ these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age.

High incidence of amyotrophic lateral sclerosis in the Faroe Islands 2010-2020.

The Faroese population isolate harbors epidemiological and genetic characteristics that likely differ from outbred populations. This population-based register study found that the Faroese 2010-2020 crude incidence of amyotrophic lateral sclerosis (ALS) was 4.9/100,000 person-years (95% confidence interval [CI], 3.3-7.0) and the age- and sex-standardized incidence (US 2010 Census Population) was 4.1/100,000 person-years (95% CI, 2.7-6.0), which is a 68% increase from the 1987-2009 estimate. The 2020 crude prevalence was 9.5/100,000 (95% CI, 3.0-19.6) in a population of 52,912 inhabitants. Incidence and prevalence estimates of ALS in the Faroes are high and further research is warranted to uncover the genetic or environmental determinants of ALS in this population.

Prevalence of Open-angle Glaucoma in the Faroese Population.

PURPOSE: The Faroe Islands are home to 50,000 genetically isolated people in the North Atlantic. The prevalence of open-angle glaucoma (OAG) in the Faroese population is unknown. Consequently, we conducted a survey to determine the prevalence of OAG in the Faroese population. We also investigated the role of known glaucoma-causing genes in Faroese OAG. MATERIALS AND METHODS: We conducted a prospective survey of known and newly diagnosed glaucoma patients at the Faroese National Hospital, Landssjukrahusid, Tórshavn between October 1, 2015 to December 31, 2017. In addition we reviewed the only eye care provider in the Faroese Islands by scrutinizing electronic medical records between 2009 and June 15, 2014, October 1, 2015 and the partly overlapping prescriptions for ocular hypotensive medications in 2016 to identify patients with either a diagnosis of glaucoma, a diagnosis of ocular hypertension or a prescription for ocular hypotensive medications. Next, we prospectively confirmed diagnoses with complete eye examinations. Patient DNA samples were tested for variations in known glaucoma-causing genes [myocilin (MYOC), optineurin (OPTN), and TANK binding kinase 1 (TBK1)]. RESULTS: We determined the age-related prevalence of OAG January 1, 2017 in individuals 40 years or older to be 10.7/1000 (1.07%) and highly age-related. A diagnosis of OAG was present in 264 patients, of whom 211 (79.9%) had primary OAG (including normal tension glaucoma), 49 (18.6%) had pseudoexfoliation glaucoma, and 4 (1.5%) had pigmentary glaucoma. Among patients receiving medications for glaucoma, nearly 50% had primary OAG, while the majority of the rest had ocular hypertension or secondary glaucoma. No disease-causing variants were detected in MYOC, OPTN, or TBK1. CONCLUSIONS: The calculated prevalence of OAG in the Faroe Islands was 1.07%. The absence of MYOC, OPTN, or TBK1 disease-causing variants in Faroese primary OAG patients suggests that a different, potentially unique set of genes may be contributing to the pathogenesis of glaucoma in this population.

FarGen - participants in the genetic research infrastructure of the Faroe Islands.

Background: The demographic history of the Faroe Islands makes this isolated population - founded in the 9th century - interesting for genetic research. The goal of the FarGen project was to recruit individuals to the FarGen infrastructure to promote research into the genetic features of the Faroese people, and to develop a reference panel of population-specific variants. We aimed to recruit 1500 individuals. Participation was voluntary; participants had to donate a blood sample for whole-genome sequencing, and had to answer a questionnaire regarding sociodemographics, health, motivation and attitude towards participation in genetic research. Methods: A total of 1541 participants voluntarily joined the project, donated a blood sample and returned the questionnaire. Results: Answers from the questionnaire show that participants are, in general, European, have children, have a relatively high level of education, rate their health to be good, are willing to participate in future health-related research, and were motivated to sign up primarily to participate in research to help others and local research competency building. Conclusions: Overall, the initial cohort of the FarGen infrastructure comprises 3% of the Faroese population, and represents the general population well based on the collected sociodemographic data. However, there is an excess of women, and some geographic sub-regions and age groups are slightly underrepresented. We find the recruitment method with voluntary sign-up appropriate, and knowledge acquired through the first phase will aid the next phase of the project, with the aim of expanding the FarGen cohort with additional individuals, bio-specimens and body measurements in order to perform multifactorial analyses.

Amyotrophic lateral sclerosis in the Faroe Islands - a genealogical study.

In the Faroe Islands, a clustering of amyotrophic lateral sclerosis (ALS) was observed on the geographically isolated island, Suðuroy. This study aims to estimate the frequency of familial ALS (fALS) in the Faroes including 43 patients diagnosed with ALS. Patients with fALS were identified through medical records and the Faroese Multi Generation Register. Firstly, fALS was recognized when occurring between first- or second-degree relatives. Secondly, families and individuals with fALS were recognized through pedigrees (≥3 cases within 3 generations). The prevalence of ALS was 3 times higher in Suðuroy compared to the nationwide prevalence. The frequency of fALS was at least 14% (n = 6) and mean survival time was 1.7 years shorter for fALS compared to sporatic ALS (p = 0.01. SD = 0.5, range 1.0-2.2). This study is suggestive of familial clustering in excess of expected for ALS and supports a genetic contribution to ALS in the Faroe Islands albeit environmental exposure within families cannot be excluded.

PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome.

We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.

Using dried blood spot samples from a trio for linked-read whole-exome sequencing.

Long-term collection of dried blood spot (DBS) samples through newborn screening may have retrospective and prospective advantages, especially in combination with advanced analytical techniques. This work concerns whether linked-reads may overcome some of the limitations of short-read sequencing of DBS samples, such as performing molecular phasing. We performed whole-exome sequencing of DNA extracted from DBS and corresponding whole blood (WB) reference samples, belonging to a trio with unaffected parents and a proband affected by primary carnitine deficiency (PCD). For the DBS samples we were able to phase >21% of the genes under 100 kb, >40% of the SNPs, and the longest phase block was >72 kb. Corresponding results for the WB reference samples was >85%, >75%, and >915 kb, respectively. Concerning the PCD causing variant (rs72552725:A > G) in the SLC22A5 gene we observe full genotype concordance between DBS and WB for all three samples. Furthermore, we were able to phase all variants within the SLC22A5 gene in the proband's WB data, which shows that linked-read sequencing may replace the trio information for haplotype detection. However, due to smaller molecular lengths in the DBS data only small phase blocks were observed in the proband's DBS sample. Therefore, further optimisation of the DBS workflow is needed in order to explore the full potential of DBS samples as a test bed for molecular phasing.

Both rare and common genetic variants contribute to autism in the Faroe Islands.

The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions (p = 0.0352) or duplications (p = 0.0352)), higher inbreeding status (p = 0.023) and a higher load of rare homozygous deleterious variants (p = 0.011) compared to controls. Our analysis supports the role of several genes/loci associated with autism (e.g., NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g., GRIK2, ROBO1, NINL, and IMMP2L) or recessive deleterious variants (e.g., KIRREL3 and CNTNAP2) affecting autism-associated genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN, and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.

Vitamin d in the general population of young adults with autism in the faroe islands.

Vitamin D deficiency has been proposed as a possible risk factor for developing autism spectrum disorder (ASD). 25-Hydroxyvitamin D3 (25(OH)D3) levels were examined in a cross-sectional population-based study in the Faroe Islands. The case group consisting of a total population cohort of 40 individuals with ASD (aged 15-24 years) had significantly lower 25(OH)D3 than their 62 typically-developing siblings and their 77 parents, and also significantly lower than 40 healthy age and gender matched comparisons. There was a trend for males having lower 25(OH)D3 than females. Effects of age, month/season of birth, IQ, various subcategories of ASD and Autism Diagnostic Observation Schedule score were also investigated, however, no association was found. The very low 25(OH)D3 in the ASD group suggests some underlying pathogenic mechanism.

Autism in the Faroe Islands: diagnostic stability from childhood to early adult life.

Childhood autism or autism spectrum disorder (ASD) has been regarded as one of the most stable diagnostic categories applied to young children with psychiatric/developmental disorders. The stability over time of a diagnosis of ASD is theoretically interesting and important for various diagnostic and clinical reasons. We studied the diagnostic stability of ASD from childhood to early adulthood in the Faroe Islands: a total school age population sample (8-17-year-olds) was screened and diagnostically assessed for AD in 2002 and 2009. This paper compares both independent clinical diagnosis and Diagnostic Interview for Social and Communication Disorders (DISCO) algorithm diagnosis at two time points, separated by seven years. The stability of clinical ASD diagnosis was perfect for AD, good for "atypical autism"/PDD-NOS, and less than perfect for Asperger syndrome (AS). Stability of the DISCO algorithm subcategory diagnoses was more variable but still good for AD. Both systems showed excellent stability over the seven-year period for "any ASD" diagnosis, although a number of clear cases had been missed at the original screening in 2002. The findings support the notion that subcategories of ASD should be collapsed into one overarching diagnostic entity with subgrouping achieved on other "non-autism" variables, such as IQ and language levels and overall adaptive functioning.