Biology subjects
Publications and source records attributed to Gudjonsson, S. A..
The authors have withdrawn this manuscript because this paper was posted prematurely in advance of a UK Biobank Pharma Proteomics Project consortium effort. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author
We describe the analysis of whole genome sequences (WGS) of 150,119 individuals from the UK biobank (UKB). This constitutes a set of high quality variants, including 585,040,410 SNPs, representing 7.0% of all possible human SNPs, and 58,707,036 indels. The large set of variants allows us to characterize selection based on sequence variation within a population through a Depletion Rank (DR) score for windows along the genome. DR analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UKB, a large British Irish cohort (XBI) and smaller African (XAF) and South Asian (XSA) cohorts. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large scale WGS studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on exome sequencing and/or imputation.
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{middle dot}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{middle dot}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.
De novo mutations (DNMs) cause a large fraction of severe rare diseases of childhood. DNMs that occur in early embryos may result in mosaicism of both somatic and germ cells. Such early mutations may be transmitted to more than one offspring and cause recurrence of serious disease. We scanned 1,007 sibling pairs from 251 families and identified 885 DNMs shared by siblings (ssDNMs) at 451 genomic sites. We estimated the probability of DNM recurrence based on presence in the blood of the parent, sharing by other siblings, parent-of-origin, mutation type, and genomic position. We detected 52.1% of ssDNMs in the parental blood. The probability of a DNM being shared goes down by 2.28% per year for paternal DNMs and 1.82% for maternal DNMs. Shared paternal DNMs are more likely to be T>C mutations than maternal ones, but less likely to be C>T mutations. Depending on DNM properties, the probability of recurrence in a younger sibling ranges from 0.013% to 29.6%. We have launched an online DNM recurrence probability calculator, to use in genetic counselling in cases of rare genetic diseases.