Bjarni A. Atlason

Long-read sequencing (LRS) promises to improve characterization of structural variants (SVs), a major source of genetic diversity. We generated LRS data on 3,622 Icelanders using Oxford Nanopore Technologies, and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions), spanning a median of 10 Mb per haploid genome. We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association with a rare (AF = 0.037%) deletion of the first exon of PCSK9 . Carriers of this deletion have 0.93 mmol/L (1.31 SD) lower LDL cholesterol levels than the population average (p-value = 7.0·10 −20 ). We also discovered an association with a multi-allelic SV inside a large repeat region, contained within single long reads, in an exon of ACAN . Within this repeat region we found 11 alleles that differ in the number of a 57 bp-motif repeat, and observed a linear relationship (0.016 SD per motif inserted, p = 6.2·10 −18 ) between the number of repeats carried and height. These results show that SVs can be accurately characterized at population scale using long read sequence data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.

BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.