GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

© 2019, The Author(s). Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density

Does Sex-Selective Predation Stabilize or Destabilize Predator-Prey Dynamics?

Background: Little is known about the impact of prey sexual dimorphism on predator-prey dynamics and the impact of sexselective harvesting and trophy hunting on long-term stability of exploited populations. Methodology and Principal Findings: We review the quantitative evidence for sex-selective predation and study its longterm consequences using several simple predator-prey models. These models can be also interpreted in terms of feedback between harvesting effort and population size of the harvested species under open-access exploitation. Among the 81 predator-prey pairs found in the literature, male bias in predation is 2.3 times as common as female bias. We show that long-term effects of sex-selective predation depend on the interplay of predation bias and prey mating system. Predation on the ‘less limiting’ prey sex can yield a stable predator-prey equilibrium, while predation on the other sex usually destabilizes the dynamics and promotes population collapses. For prey mating systems that we consider, males are less limiting except for polyandry and polyandrogyny, and male-biased predation alone on such prey can stabilize otherwise unstable dynamics. On the contrary, our results suggest that female-biased predation on polygynous, polygynandrous or monogamous prey requires other stabilizing mechanisms to persist. Conclusions and Significance: Our modelling results suggest that the observed skew towards male-biased predation might reflect, in addition to sexual selection, the evolutionary history of predator-prey interactions. More focus on these phenomena can yield additional and interesting insights as to which mechanisms maintain the persistence of predator-prey pairs over ecological and evolutionary timescales. Our results can also have implications for long-term sustainability of harvesting and trophy hunting of sexually dimorphic species

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart

The genetic epidemiology of joint shape and the development of osteoarthritis

Congruent, low-friction relative movement between the articulating elements of a synovial joint is an essential pre-requisite for sustained, efficient, function. Where disorders of joint formation or maintenance exist, mechanical overloading and osteoarthritis (OA) follow. The heritable component of OA accounts for ~ 50% of susceptible risk. Although almost 100 genetic risk loci for OA have now been identified, and the epidemiological relationship between joint development, joint shape and osteoarthritis is well established, we still have only a limited understanding of the contribution that genetic variation makes to joint shape and how this modulates OA risk. In this article, a brief overview of synovial joint development and its genetic regulation is followed by a review of current knowledge on the genetic epidemiology of established joint shape disorders and common shape variation. A summary of current genetic epidemiology of OA is also given, together with current evidence on the genetic overlap between shape variation and OA. Finally, the established genetic risk loci for both joint shape and osteoarthritis are discussed

Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene.

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 DownloadPredicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.Sacchi Foundatio

Variant ASGR1 associated with a reduced risk of coronary artery disease

BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Funding Information: This work was supported by grants from the Knut and Alice Wallenberg Foundation (2012.0193 and 2017.0436), the Swedish Research Council (2017-02023 and 2018-00424), the Swedish Cancer Society (2017/265), the Nordic Cancer Union (R217-A13329-18-S65), Arne and Inga-Britt Lundberg’s Stiftelse (2017-0055), European Research Council (EU-MSCA-COFUND 754299 CanFaster), Myeloma UK and Cancer Research UK (C1298/A8362), The National Institute of Health (R01 DK103794 and R01HL146500), the New York Stem Cell Foundation, a gift from the Lodish Family to Boston Children’s Hospital, and Mr. Ralph Stockwell. We thank Ellinor Johnsson for her assistance between 2011 and 2020. We are indebted to the patients who participated in the study. Publisher Copyright: © 2022, The Author(s).Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.Peer reviewe

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Funding Information: Funding The study was funded by NORDFORSK (grant agreement no. 90825, project NORA), the Swedish Research Council (2018-02803), the Swedish innovation Agency (Vinnova), Innovationsfonden and The Research Council of Norway, Region Stockholm-Karolinska Institutet and Region Västerbotten (ALF), the Danish Rheumatism Association (R194-A6956), the Swedish Brain Foundation, Nils and Bibbi Jensens Foundation, the Knut and Alice Wallenberg Foundation, Margaretha af Ugglas Foundation, the South-Eastern Heath Region of Norway, the Health Research Fund of Central Denmark Region, Region of Southern Denmark, the A.P. Moller Foundation for the Advancement of Medical Science, the Colitis-Crohn Foreningen, the Novo Nordisk Foundation (NNF15OC0016932), Aase og Ejnar Danielsens Fond, Beckett-Fonden, Augustinus Fonden, Knud and Edith Eriksens Mindefond, Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis’ Legat, the Psoriasis Forskningsfonden, the University of Aarhus, the Danish Rheumatism Association (R194-A6956, A1923, A3037 and A3570 – www. gigtforeningen.dk), Region of Southern Denmark’s PhD Fund, 12/7725 (www.regionsyddanmark.dk) and the Department of Rheumatology, Frederiksberg Hospital (www.frederiksberghospital. dk). MoBa Genetics has been funded by the Research Council of Norway (#229624, #223273), South East and Western Norway Health Authorities, ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Novo Nordisk Foundation and the University of Bergen. KB and SB acknowledge the Novo Nordisk Foundation (grant NNF14CC0001). Funding Information: competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer; OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB; and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. Publisher Copyright: © Funding Information: Funding The study was funded by NORDFORSK (grant agreement no. 90825, project NORA), the Swedish Research Council (2018-02803), the Swedish innovation Agency (Vinnova), Innovationsfonden and The Research Council of Norway, Region Stockholm-Karolinska Institutet and Region Västerbotten (ALF), the Danish Rheumatism Association (R194-A6956), the Swedish Brain Foundation, Nils and Bibbi Jensens Foundation, the Knut and Alice Wallenberg Foundation, Margaretha af Ugglas Foundation, the South-Eastern Heath Region of Norway, the Health Research Fund of Central Denmark Region, Region of Southern Denmark, the A.P. Moller Foundation for the Advancement of Medical Science, the Colitis-Crohn Foreningen, the Novo Nordisk Foundation (NNF15OC0016932), Aase og Ejnar Danielsens Fond, Beckett-Fonden, Augustinus Fonden, Knud and Edith Eriksens Mindefond, Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis’ Legat, the Psoriasis Forskningsfonden, the University of Aarhus, the Danish Rheumatism Association (R194-A6956, A1923, A3037 and A3570 – www. gigtforeningen.dk), Region of Southern Denmark’s PhD Fund, 12/7725 (www.regionsyddanmark.dk) and the Department of Rheumatology, Frederiksberg Hospital (www.frederiksberghospital. dk). MoBa Genetics has been funded by the Research Council of Norway (#229624, #223273), South East and Western Norway Health Authorities, ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Novo Nordisk Foundation and the University of Bergen. KB and SB acknowledge the Novo Nordisk Foundation (grant NNF14CC0001). Funding Information: competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer; OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB; and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. Publisher Copyright: ©Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.Peer reviewe

Molecular benchmarks of a SARS-CoV-2 epidemic.

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 DownloadA pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures

Late Weichselian history of relative sea level changes in Iceland during a collapse and subsequent retreat of marine based ice sheet

At the Last Glacial Maximum, Iceland was covered by an ice sheet more than 2000 m thick reaching as far as the shelf break. Rapid deglaciation, controlled by rising global sea level, started between 18.6 and 15.0 cal kyrs BP. In Bølling times, between 15.0 and 14.7 cal kyrs BP, the marine based part of the ice sheet collapsed and glaciers retreated inside the present coastline. At that time Marine Limit (ML) shorelines at very high altitudes were formed. Due to low viscosity of the mantel underneath Iceland, isostatic recovery was very rapid and there is a clear link between deglaciation, glacial unloading and volcanic activity. Following climatic deterioration the ice sheet re-advanced during the Younger Dryas, between 13.8 and 12.0 cal kyrs BP. The advance was terminated near the present coastline as distinct shorelines at lower altitudes than before were formed. In Early Preboreal times, about 11.2 cal kyrs BP, the ice sheet re-advanced once again and a new set of distinct shorelines was formed, at still lower altitudes than before. After that the ice sheet retreated rapidly and relative sea level fell towards and eventually below present sea level, reaching a minimum at -44 m at about 10.0 cal kyrs BP. At about 8.7 cal kyrs BP the ice sheet had disintegrated into individual icecaps of similar extent as the present glaciers.A finales del Último Máximo Glacial, Islandia estaba cubierta por una capa de hielo de más de 2000 m de espesor, llegando hasta la ruptura de la plataforma continental. Una deglaciación rápida, controlada por el ascenso global del nivel del mar, comenzó entre 18,6 y 15,0 cal kyrs BP. Durante el Bølling, entre 15,0 y 14,7 cal kyrs BP, la parte marina del manto de hielo colapsó y los glaciares se retiraron al interior de la actual línea de costa. En ese momento se formaron líneas de playa correspondientes al Límite Marino a elevadas alturas. Debido a la baja viscosidad del manto por debajo de Islandia, la recuperación isostática fue muy rápida, de manera que hay una estrecha relación entre deglaciación, descarga glacial y actividad volcánica. Después del deterioro climático, la capa de hielo experimentó un reavance durante el Younger Dryas, entre 13,8 y 12,0 cal kyrs BP. El avance terminó cerca de la costa actual, pues se formaron distintas líneas de playa a menores alturas que las anteriores. A comienzos del Preboreal, hacia 11,2 cal kyrs BP, la capa de hielo tuvo un nuevo reavance, formándose un nuevo conjunto de líneas de costa, a alturas todavía inferiores que las anteriores. Después el hielo se retiró rápidamente y el nivel del mar relativo cayó hasta e incluso por debajo de actual nivel del mar, alcanzando un mínimo de -44 m hacia 10,0 cal kyrs BP. Hacia 8,7 cal kyrs BP el manto de hielo se desintegró en casquetes individuales de extensión similar a los actuales glaciares