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.

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.

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.