Sigurgeir Ólafsson
A5008553103- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- DNA Repair Mechanisms
- Genetic Associations and Epidemiology
- Immune Cell Function and Interaction
- Genomics and Rare Diseases
- Evolution and Genetic Dynamics
- T-cell and B-cell Immunology
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Inflammatory Bowel Disease
- CRISPR and Genetic Engineering
- Lymphoma Diagnosis and Treatment
- Colorectal Cancer Treatments and Studies
- Acute Myeloid Leukemia Research
- Diverticular Disease and Complications
- Study of Mite Species
- Urinary and Genital Oncology Studies
- Systemic Lupus Erythematosus Research
- BRCA gene mutations in cancer
- Microscopic Colitis
- Helicobacter pylori-related gastroenterology studies
- Cognitive Abilities and Testing
- Gastrointestinal motility and disorders
- Cutaneous lymphoproliferative disorders research
- Cleft Lip and Palate Research
Wellcome Sanger Institute
2019-2023
deCODE Genetics (Iceland)
2016-2023
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 particularly affected displays methylation-sensitive regulatory properties vitro. Causal inference Mendelian randomization provide evidence HLA variants mediate MS via changes DMR modify expression. Meta-analysis...
Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with combination genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection strong suspect. We have previously identified increased autoantibody levels toward chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity ANO2 EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology plasma samples from 8,746 MS cases...
Inflammatory bowel disease (IBD) is a chronic inflammatory associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 41 non-IBD controls our previous publication on the mutation landscape normal colon. The average rate affected epithelial cells 2.4-fold that healthy colon, this increase mostly driven by acceleration mutational processes ubiquitously observed in In contrast where clonal expansions...
Abstract Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε δ replicate during cell division. However, some cancers, defective proofreading due acquired POLE / POLD1 exonuclease domain mutations causes markedly elevated mutation burdens with distinctive mutational signatures. Germline familial predisposition. Here, we sequenced normal tissue tumor from individuals germline mutations. Increased characteristic...
Abstract We use polygenic risk scores (PRSs) for schizophrenia (SCZ) and bipolar disorder (BPD) to predict smoking, addiction nicotine, alcohol or drugs in individuals not diagnosed with psychotic disorders. Using PRSs 144 609 subjects, including 10 036 admitted in‐patient treatment 35 754 smokers, we find that diagnoses of various substance disorders smoking associate strongly SCZ ( P = 5.3 × −50 –1.4 −6 ) BPD 1.7 −9 –1.9 −3 ), showing shared genetic etiology between psychosis addiction....
Abstract Cellular DNA damage caused by reactive oxygen species is repaired the base excision repair (BER) pathway which includes glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, mechanistic progression from germline MUTYH-Associated Polyposis (MAP) incompletely understood. Here, we sequence normal tissue DNAs 10 individuals with MAP. Somatic substitution mutation rates in intestinal epithelial cells were elevated 2...
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from single hematopoietic stem cell lineage. Using whole-genome sequencing 45,510 Icelandic and 130,709 UK Biobank participants combined with mutational barcode method, we identified 16,306 people CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates dosage-dependent impact on risk CH associates several smoking-related diseases. Contrary to published claims, find no evidence...
Abstract Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association diverticular (5,426 cases) its more form diverticulitis (2,764 cases). Subsequently, 16 are followed up a sample from Denmark (5,970 cases, 3,020...
Abstract Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in DNA mismatch repair (MMR) gene. Although cancers LS patients show elevated somatic mutation burdens, information on rates normal tissues and understanding the trajectory from cell limited. Here we whole genome sequence 152 crypts neoplastic epithelial 10 patients. In repertoire mutational processes similar that found wild type individuals. A...
Abstract Microsatellites are polymorphic tracts of short tandem repeats with one to six base-pair (bp) motifs and some the most variants in genome. Using 6084 Icelandic parent-offspring trios we estimate 63.7 (95% CI: 61.9–65.4) microsatellite de novo mutations (mDNMs) per offspring generation, excluding bp (homopolymers) is 48.2 mDNMs 46.7–49.6). Paternal occur at longer than maternal ones, which turn larger a mean size 3.4 vs 3.1 for paternal ones. increase by 0.97 0.90–1.04) 0.31...
We present association results from a large genome-wide study of tooth agenesis (TA) as well selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all European ancestry. also tested the previously identified risk variants, for timing eruption orofacial clefts, TA. report associations between TA 9 novel variants. Five these variants associate variant conferring clefts. These contribute to deeper understanding genetic architecture...
Abstract The persistence of common, heritable psychiatric disorders that reduce reproductive fitness is an evolutionary paradox. Here, we investigate the selection pressures on sequence variants predispose to schizophrenia, autism, bipolar disorder, major depression and attention deficit hyperactivity disorder (ADHD) using genomic data from 150,656 Icelanders, excluding those diagnosed with these diseases. Polygenic risk autism ADHD associated number children. Higher polygenic fewer children...
A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating sclerosis, not reported previously. Using polygenic risk scores based public outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As...
Abstract Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis 111 patients with psoriasis search for evidence that somatic keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no large-scale spread clones carrying potentially pathogenic mutations. The mutation rate was similarly only modestly affected by...
ABSTRACT Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases Pol ε δ replicate with high fidelity during cell divisions. However, some cancers defective proofreading due acquired mutations the exonuclease domains POLE or POLD1 causes markedly elevated mutation burdens distinctive mutational signatures. domain also familial predisposition when inherited through germline. Here, we sequenced tissue from...
Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, alkaline phosphatase (ALP) are widely measured in attempts to detect monitor treatment response. However, due lack of sensitivity specificity, their utility is debated. The serum levels these markers affected by a number nonmalignant factors, including genotype. Thus, it may be possible improve both specificity adjusting test results for genetic effects.We performed genome-wide association studies AFP (N...
The plant parasitic mite Penthaleus major (Dugès) occurs as a pest on perennial grasses in hayfields Iceland, northern Norway, and southern Greenland. In these areas it appears summer phenomenon, contrary to more locations, where winter crops. Up 500 individuals of P. were collected per day pitfall traps. Spring application 44 ml/ha permethrin 5 ml deltamethrin significantly reduced but did not eliminate the populations following weeks. addition this immediate effect, spring also decreased...
Abstract Only a few common variants in the sequence of genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores educational attainment predict specific aspects childhood cognition, as measured with IQ. Recently, three were associate attainment, confluence phenotype genetic and environmental factors contributing academic success. We show one these associating rs4851266-T, also associates Verbal IQ dyslexic children ( P = 4.3 × 10 −4 , β 0.16 s.d.). The...
The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in blood. As some these are strongly correlated, it important evaluate independent effects they may have on survival.Tumour samples from 2162 CRC patients were visually assessed for amount stroma, severity lymphocytic infiltrate at margins presence lymphoid follicles. Somatic 2134 individuals....
ABSTRACT Cellular DNA damage caused by reactive oxygen species is repaired the base excision repair (BER) pathway which includes glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, mechanistic progression from germline M UTYH- A ssociated P olyposis (MAP) incompletely understood. Here, we sequenced normal tissue DNAs 10 individuals with MAP. Somatic substitution mutation rates in intestinal epithelial cells were elevated...
Abstract Somatic mutations are hypothesised to play a role in many non-neoplastic diseases. These diseases may also shape the somatic mutation landscape of affected tissues after onset. We performed whole-exome sequencing 1182 microbiopsies dissected from lesional and non-lesional epidermis 111 patients with psoriasis, chronic inflammatory disease skin, search for evidence that keratinocytes influence process characterise effects on epidermis. show psoriasis is associated increased burden...