38 research outputs found
COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA
Background: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been
shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a
dominant mode of inheritance.
Case presentation: Here we describe an Icelandic family with three affected individuals over two generations with
a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed
whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched
for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all
coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a
heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The
mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic
genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs
within the conserved and functionally important WD40 domain of the COPA protein.
Conclusions: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the
mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five
affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and
its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome.
Keywords: COPA syndrome, Lung disease, Arthritis, Immune dysregulation, Case reportPeer Reviewe
Whole genome characterization of sequence diversity of 15,220 Icelanders
Understanding of sequence diversity is the cornerstone of analysis of genetic disorders, population genetics, and evolutionary biology. Here, we present an update of our sequencing set to 15,220 Icelanders who we sequenced to an average genome-wide coverage of 34X. We identified 39,020,168 autosomal variants passing GATK filters: 31,079,378 SNPs and 7,940,790 indels. Calling de novo mutations (DNMs) is a formidable challenge given the high false positive rate in sequencing datasets relative to the mutation rate. Here we addressed this issue by using segregation of alleles in three-generation families. Using this transmission assay, we controlled the false positive rate and identified 108,778 high quality DNMs. Furthermore, we used our extended family structure and read pair tracing of DNMs to a panel of phased SNPs, to determine the parent of origin of 42,961 DNMs.Peer Reviewe
Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants 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 multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio
Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Publisher's version (útgefin grein)Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3‘ UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.We thank the individuals who participated in this study and the staff at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities. Further to all our colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK biobank Resource under Application Number ‘24711’.Peer Reviewe
A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
Publisher's version (útgefin grein)
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are
recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in
humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox)
and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous
loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chipgenotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting
as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst.
Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD)
in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm).
Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct
profile of infections indicative of macrophage dysfunction.We wish to thank the family of the two probands, as well as all the other individuals who
participated in the study and whose contribution made this work possible.Peer Reviewe
Rings of differential operators and étale homomorphisms
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mathematics, 1991.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Includes bibliographical references (p. 130-132).by Gísli Másson.Ph.D
Weighting sequence variants based on their annotation increases power of whole-genome association studies.
To access publisher's full text version of this article click on the hyperlink at the bottom of the pageThe consensus approach to genome-wide association studies (GWAS) has been to assign equal prior probability of association to all sequence variants tested. However, some sequence variants, such as loss-of-function and missense variants, are more likely than others to affect protein function and are therefore more likely to be causative. Using data from whole-genome sequencing of 2,636 Icelanders and the association results for 96 quantitative and 123 binary phenotypes, we estimated the enrichment of association signals by sequence annotation. We propose a weighted Bonferroni adjustment that controls for the family-wise error rate (FWER), using as weights the enrichment of sequence annotations among association signals. We show that this weighted adjustment increases the power to detect association over the standard Bonferroni correction. We use the enrichment of associations by sequence annotation we have estimated in Iceland to derive significance thresholds for other populations with different numbers and combinations of sequence variants
Supplementary Figure 13. MDS plots with African reference populations (Affymetrix)
Plots showing the first two dimensions of an MDS analysis with HJ’s reconstructed maternal genome along with (a) African reference populations and (b) West African reference populations typed on the Affymetrix platforms