Multiple genetic loci for bone mineral density and fractures

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. METHODS: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). RESULTS: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11. CONCLUSIONS: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis

Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesEpileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesBackground: 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

A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadThe cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in EPOR, carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF = 0.09%, Effect = 1.47 SD, P = 3.3 × 10-7). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls (P = 1.7 × 10-6; Pcombined = 1.6 × 10-11). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect = -0.045 SD, P = 0.32, N = 273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness

Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis

Funding Information: The authors thank the subjects who have donated their time and their samples that were used in this research. Publisher Copyright: © 2023, The Author(s).Background: 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 the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival. Methods: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH). Results: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis. Conclusions: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.Peer reviewe

Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMalignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.deCODE Genetics/Amgen Inc

The sequences of 150,119 genomes in the UK Biobank

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data(1,2). Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank(3). This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank 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 UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. 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 whole-genome sequencing 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 whole-exome sequencing and/or imputation

HLA alleles, disease severity, and age associate with T-cell responses following infection with SARS-CoV-2

Funding Information: We thank all of the participants that contributed samples for this study for their invaluable contribution to the research. We also thank our research staff at the Patient Recruitment Center for their thorough work. Publisher Copyright: © 2022, The Author(s).Memory T-cell responses following SARS-CoV-2 infection have been extensively investigated but many studies have been small with a limited range of disease severity. Here we analyze SARS-CoV-2 reactive T-cell responses in 768 convalescent SARS-CoV-2-infected (cases) and 500 uninfected (controls) Icelanders. The T-cell responses are stable three to eight months after SARS-CoV-2 infection, irrespective of disease severity and even those with the mildest symptoms induce broad and persistent T-cell responses. Robust CD4+ T-cell responses are detected against all measured proteins (M, N, S and S1) while the N protein induces strongest CD8+ T-cell responses. CD4+ T-cell responses correlate with disease severity, humoral responses and age, whereas CD8+ T-cell responses correlate with age and functional antibodies. Further, CD8+ T-cell responses associate with several class I HLA alleles. Our results, provide new insight into HLA restriction of CD8+ T-cell immunity and other factors contributing to heterogeneity of T-cell responses following SARS-CoV-2 infection.Peer reviewe

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p