Þorvaldur Ingvarsson - Academia.edu (original) (raw)
Papers by Þorvaldur Ingvarsson
Journal of Bone and Mineral Research, Aug 29, 2015
We conducted a genome-wide association study of low BMD at the hip and spine utilizing sequence v... more We conducted a genome-wide association study of low BMD at the hip and spine utilizing sequence variants found through whole-genome sequencing of 2,636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low bone mineral density (BMD) and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (P = 1.8 × 10(-7) , OR = 4.61 (95% CI 2.59, 8.18)) whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (P = 1.9 × 10(-8) , OR = 9.34 (4.28, 20.3)). Association with fractures was P = 2.2 × 10(-5) , OR = 3.75 (2.03, 6.93) and P = 0.0023, OR = 4.32 (1.69, 11.1), respectively. The carriers of these variants do not have other signs of osteogenesis imperfecta than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way. This article is protected by copyright. All rights reserved.
The New England Journal of Medicine, May 29, 2008
Background Bone mineral density influences the risk of osteoporosis later in life and is useful i... more Background 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, 1.2×10 −7 to 2.0×10 −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-κB 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-κB 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.
Nature Biomedical Engineering, May 31, 2021
Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the use... more Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the user as belonging to their own body. Robotic limbs can convey information about the environment with higher precision than biological limbs, but their actual performance is substantially limited by current technologies for the interfacing of the robotic devices with the body and for transferring motor and sensory information bidirectionally between the prosthesis and the user. In this Perspective, we argue that direct skeletal attachment of bionic devices via osseointegration, the amplification of neural signals by targeted muscle innervation, improved prosthesis control via implanted muscle sensors and advanced algorithms, and the provision of sensory feedback by means of electrodes implanted in peripheral nerves, should all be leveraged toward the creation of a new generation of highperformance bionic limbs. These five technologies have been clinically tested in humans, and alongside mechanical redesigns and adequate rehabilitation training should facilitate the wider clinical use of bionic limbs. Prosthetics aim to substitute the loss of an extremity via technological means. Missing a limb leads to significant impairments in the capacity to move and to interact with the environment. This deficiency is associated with the actual functional loss of a body part and with the loss of sensation, and it can also
Birkhäuser Basel eBooks, 2002
To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis ... more To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis (OA) leading to total hip replacement (THR). Information from 2 population-based databases in Iceland was combined: a national registry of all THRs performed between 1972 and 1996, and a genealogy database of all available Icelandic genealogy records for the last 11 centuries. A genetic contribution to THR for OA was assessed by 1) identifying familial clusters of OA patients with THR, 2) applying the minimum founder test (MFT) to estimate the minimum number of ancestors (&amp;amp;amp;quot;founders&amp;amp;amp;quot;) that would account for the genealogy of all 2,713 patients with THR for OA, compared with the average number of founders for control lists, 3) calculating an average pairwise kinship coefficient (KC) for the patient list and control lists, and 4) estimating the relative risk (RR) for THR among relatives of OA patients who have undergone the procedure. One thousand matched control lists, each the same size as the patient list, were created using the genealogy database. A large number of familial clusters of patients with THR for OA were identified. The MFT showed that OA patients descended from fewer founders than did subjects in the control groups (P &amp;amp;amp;lt; 0.001). The average pairwise KC among patients with OA was greater than in the control population (P &amp;amp;amp;lt; 0.001). The RR for THR among siblings of OA patients was 3.05 (95% confidence interval 2.52-3.10). This population-based study shows that Icelandic patients with hip replacement for OA are significantly more related to each other than are matched controls drawn from the Icelandic population. These findings support a significant genetic contribution to a common form of OA and encourage the search for genes conferring an increased susceptibility to OA.
Læknafélag Íslands, Læknafélag Reykjavíkur, Dec 1, 2004
Journal of Medical Genetics, Dec 16, 2013
Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral dens... more Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10 −5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
Nature Communications, Jan 6, 2016
Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of f... more Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4-22.6%) that associates with reduced spine BMD (P ¼ 1.0 Â 10 À 11 , b ¼ À 0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P ¼ 6.6 Â 10 À 10 , b ¼ 0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus.
Nature Communications, May 3, 2019
Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometr... more 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.
Acta Orthopaedica, 2006
The national hip registers of the Nordic countries provide an opportunity to compare age- and sex... more The national hip registers of the Nordic countries provide an opportunity to compare age- and sex-standardized annual incidence of primary total hip replacement (THR) and types of implants used for primary hip osteoarthritis (OA) in Denmark, Finland, Iceland, Norway and Sweden. The data on THR were from the national total hip replacement registries, and population data were from the national statistics agencies. Annual incidence density per 100,000 was calculated for each 5-year age group and it was age-standardized using the WHO European standard population. Crude country-specific annual incidence (all ages) for 1996-2000 varied between 73 and 90. WHO age-standardized annual incidence (all ages) varied between 61 (Finland) and 84 (Iceland). For the ages 50-89, comprising 94-98% of all THRs for OA, annual incidence varied between 217 (Finland) and 309 (Iceland). For Norway, the sex incidence ratio (women/men) was 2, and for the other countries it was between 1.1 and 1.3. The use of uncemented and hybrid replacements was considerably higher in Finland and Denmark than in the other countries. We found overall similarity in THR incidence between the 5 Nordic countries, but substantial differences between women and men, and in the use of different types of implant. Population-based, age-standardized and disease-specific information on THR incidence is required in order to properly explore the causes of differences in provision and practice of THR in different countries, regions and groups, and it will aid in projecting future needs.
Nature Genetics, Mar 20, 2017
We performed a genome-wide association study of total hip replacements, based on variants identif... more We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement; a missense mutation, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12 , OR = 16.7), and a frameshift mutation, rs532464664 (p.Val330GlyfsTer106) in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18 and OR = 7.71). c.1141G>C heterozygotes and individuals homozygous for rs532464664 have their hip replacement operation 13.5 years and 4.9 years younger than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense mediated decay of the mutated transcripts.
Nature Genetics, Apr 15, 2012
Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the lar... more Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of lowtrauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10 −8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10 −4 , Bonferroni corrected), of which six reached P<5×10 −8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
International Orthopaedics, Oct 23, 1996
Summary. A prospective randomised study was made of 20 patients who underwent acromioplasty for t... more Summary. A prospective randomised study was made of 20 patients who underwent acromioplasty for the chronic impingement syndrome. Ten were operated on by Neer’s technique and 10 with a modification where the deltoid origin was spared. Rehabilitation was more rapid with a better range of movement in the latter group. Acromioplasty with this modification offers benefits compared with the standard
Annals of the Rheumatic Diseases, Mar 1, 2011
Objective-This study examines the relationship between total knee replacements (TKR),total hip re... more Objective-This study examines the relationship between total knee replacements (TKR),total hip replacements (THR) or replacements of either joint (TJR) due to osteoarthritis (OA) and atherosclerosis in a large population-based study. Methods-The participants were 2195 males and 2975 females, mean age 76±6 years. The OA data were analysed in relation to measures of atherosclerosis, including carotid artery intima media thickness and plaque severity (ultrasound), coronary and aortic calcifications (CT), cerebral white matter lesions (MRI) and history of previous cardiac and cerebral events.
Annals of the Rheumatic Diseases, Mar 16, 2013
Nature Genetics, Dec 14, 2008
In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a... more In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a follow-up in 8,510 subjects of European descent, we identified four new genomewide significant loci. These are near the SOST gene at 17q21, the MARK3 gene at 14q32, the SP7 gene at 12q13 and the TNFRSF11A (RANK) gene at 18q21. Furthermore, nonsynonymous SNPs in the C17orf53, LRP4, ADAM19 and IBSP genes were suggestively associated with bone density. Bone mineral density (BMD) is the single best predictor of fragility fractures 1,2 and is used as a reference standard for the description of osteoporosis 3. It is a highly familial quantitative trait, with heritability estimates in the range of 0.6-0.8 (ref. 4), but is also influenced by environmental and medical factors. We 5 and others 6 have recently published reports of genome-wide studies describing several loci for BMD. Both studies yielded a locus on 8q24 harboring the TNFRSF11B (also known as OPG, osteprotegerin) gene. The study by Richards et al. 6 also confirmed the welldocumented LRP5 (low-density lipoprotein receptor-related protein 5) gene 7,8 , whereas we reported loci at the TNFSF11 (also known as RANKL, receptor activator of nuclear factor kB ligand) gene (13q14), the ESR1 (estrogen receptor 1) gene (6q25), the MHC (major histocompatibility complex) region (6p21) and a locus on 1p36 that reached genome-wide significance. We also described additional loci that showed suggestive association but did not reach the genome-wide significance level, including the LRP4 (low-density lipoprotein receptor-related protein 4) gene (11p11), the TNFRSF11A (also known as RANK, receptor activator of the nuclear factor kB) gene and the SP7 (osterix) gene (12q13). We noticed a substantial excess of SNP associations compared to that expected, indicating that true additional association signals might still be found. To search for these additional variants, we expanded the genome-wide scan from 5,861 individuals
Bone, Mar 1, 2010
... involved in prevalence and progression of osteoarthritis HJM Kerkhof, I. Jonsdottir, I. Meule... more ... involved in prevalence and progression of osteoarthritis HJM Kerkhof, I. Jonsdottir, I. Meulenbelt, L. Stolk, AM Valdes, G. Zhai, Y. Zhu, M. Doherty, S. Doherty, A. Tsezou, A. Gonzalez, A. Carr, DT Felson, U. Styrkarsdottir, EP Slagboom, J. Loughlin, F. Rivadeneira, A. Hofman ...
Journal of Bone and Mineral Research, Aug 29, 2015
We conducted a genome-wide association study of low BMD at the hip and spine utilizing sequence v... more We conducted a genome-wide association study of low BMD at the hip and spine utilizing sequence variants found through whole-genome sequencing of 2,636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low bone mineral density (BMD) and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (P = 1.8 × 10(-7) , OR = 4.61 (95% CI 2.59, 8.18)) whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (P = 1.9 × 10(-8) , OR = 9.34 (4.28, 20.3)). Association with fractures was P = 2.2 × 10(-5) , OR = 3.75 (2.03, 6.93) and P = 0.0023, OR = 4.32 (1.69, 11.1), respectively. The carriers of these variants do not have other signs of osteogenesis imperfecta than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way. This article is protected by copyright. All rights reserved.
The New England Journal of Medicine, May 29, 2008
Background Bone mineral density influences the risk of osteoporosis later in life and is useful i... more Background 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, 1.2×10 −7 to 2.0×10 −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-κB 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-κB 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.
Nature Biomedical Engineering, May 31, 2021
Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the use... more Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the user as belonging to their own body. Robotic limbs can convey information about the environment with higher precision than biological limbs, but their actual performance is substantially limited by current technologies for the interfacing of the robotic devices with the body and for transferring motor and sensory information bidirectionally between the prosthesis and the user. In this Perspective, we argue that direct skeletal attachment of bionic devices via osseointegration, the amplification of neural signals by targeted muscle innervation, improved prosthesis control via implanted muscle sensors and advanced algorithms, and the provision of sensory feedback by means of electrodes implanted in peripheral nerves, should all be leveraged toward the creation of a new generation of highperformance bionic limbs. These five technologies have been clinically tested in humans, and alongside mechanical redesigns and adequate rehabilitation training should facilitate the wider clinical use of bionic limbs. Prosthetics aim to substitute the loss of an extremity via technological means. Missing a limb leads to significant impairments in the capacity to move and to interact with the environment. This deficiency is associated with the actual functional loss of a body part and with the loss of sensation, and it can also
Birkhäuser Basel eBooks, 2002
To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis ... more To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis (OA) leading to total hip replacement (THR). Information from 2 population-based databases in Iceland was combined: a national registry of all THRs performed between 1972 and 1996, and a genealogy database of all available Icelandic genealogy records for the last 11 centuries. A genetic contribution to THR for OA was assessed by 1) identifying familial clusters of OA patients with THR, 2) applying the minimum founder test (MFT) to estimate the minimum number of ancestors (&amp;amp;amp;quot;founders&amp;amp;amp;quot;) that would account for the genealogy of all 2,713 patients with THR for OA, compared with the average number of founders for control lists, 3) calculating an average pairwise kinship coefficient (KC) for the patient list and control lists, and 4) estimating the relative risk (RR) for THR among relatives of OA patients who have undergone the procedure. One thousand matched control lists, each the same size as the patient list, were created using the genealogy database. A large number of familial clusters of patients with THR for OA were identified. The MFT showed that OA patients descended from fewer founders than did subjects in the control groups (P &amp;amp;amp;lt; 0.001). The average pairwise KC among patients with OA was greater than in the control population (P &amp;amp;amp;lt; 0.001). The RR for THR among siblings of OA patients was 3.05 (95% confidence interval 2.52-3.10). This population-based study shows that Icelandic patients with hip replacement for OA are significantly more related to each other than are matched controls drawn from the Icelandic population. These findings support a significant genetic contribution to a common form of OA and encourage the search for genes conferring an increased susceptibility to OA.
Læknafélag Íslands, Læknafélag Reykjavíkur, Dec 1, 2004
Journal of Medical Genetics, Dec 16, 2013
Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral dens... more Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10 −5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
Nature Communications, Jan 6, 2016
Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of f... more Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4-22.6%) that associates with reduced spine BMD (P ¼ 1.0 Â 10 À 11 , b ¼ À 0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P ¼ 6.6 Â 10 À 10 , b ¼ 0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus.
Nature Communications, May 3, 2019
Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometr... more 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.
Acta Orthopaedica, 2006
The national hip registers of the Nordic countries provide an opportunity to compare age- and sex... more The national hip registers of the Nordic countries provide an opportunity to compare age- and sex-standardized annual incidence of primary total hip replacement (THR) and types of implants used for primary hip osteoarthritis (OA) in Denmark, Finland, Iceland, Norway and Sweden. The data on THR were from the national total hip replacement registries, and population data were from the national statistics agencies. Annual incidence density per 100,000 was calculated for each 5-year age group and it was age-standardized using the WHO European standard population. Crude country-specific annual incidence (all ages) for 1996-2000 varied between 73 and 90. WHO age-standardized annual incidence (all ages) varied between 61 (Finland) and 84 (Iceland). For the ages 50-89, comprising 94-98% of all THRs for OA, annual incidence varied between 217 (Finland) and 309 (Iceland). For Norway, the sex incidence ratio (women/men) was 2, and for the other countries it was between 1.1 and 1.3. The use of uncemented and hybrid replacements was considerably higher in Finland and Denmark than in the other countries. We found overall similarity in THR incidence between the 5 Nordic countries, but substantial differences between women and men, and in the use of different types of implant. Population-based, age-standardized and disease-specific information on THR incidence is required in order to properly explore the causes of differences in provision and practice of THR in different countries, regions and groups, and it will aid in projecting future needs.
Nature Genetics, Mar 20, 2017
We performed a genome-wide association study of total hip replacements, based on variants identif... more We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement; a missense mutation, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12 , OR = 16.7), and a frameshift mutation, rs532464664 (p.Val330GlyfsTer106) in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18 and OR = 7.71). c.1141G>C heterozygotes and individuals homozygous for rs532464664 have their hip replacement operation 13.5 years and 4.9 years younger than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense mediated decay of the mutated transcripts.
Nature Genetics, Apr 15, 2012
Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the lar... more Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of lowtrauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10 −8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10 −4 , Bonferroni corrected), of which six reached P<5×10 −8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
International Orthopaedics, Oct 23, 1996
Summary. A prospective randomised study was made of 20 patients who underwent acromioplasty for t... more Summary. A prospective randomised study was made of 20 patients who underwent acromioplasty for the chronic impingement syndrome. Ten were operated on by Neer’s technique and 10 with a modification where the deltoid origin was spared. Rehabilitation was more rapid with a better range of movement in the latter group. Acromioplasty with this modification offers benefits compared with the standard
Annals of the Rheumatic Diseases, Mar 1, 2011
Objective-This study examines the relationship between total knee replacements (TKR),total hip re... more Objective-This study examines the relationship between total knee replacements (TKR),total hip replacements (THR) or replacements of either joint (TJR) due to osteoarthritis (OA) and atherosclerosis in a large population-based study. Methods-The participants were 2195 males and 2975 females, mean age 76±6 years. The OA data were analysed in relation to measures of atherosclerosis, including carotid artery intima media thickness and plaque severity (ultrasound), coronary and aortic calcifications (CT), cerebral white matter lesions (MRI) and history of previous cardiac and cerebral events.
Annals of the Rheumatic Diseases, Mar 16, 2013
Nature Genetics, Dec 14, 2008
In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a... more In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a follow-up in 8,510 subjects of European descent, we identified four new genomewide significant loci. These are near the SOST gene at 17q21, the MARK3 gene at 14q32, the SP7 gene at 12q13 and the TNFRSF11A (RANK) gene at 18q21. Furthermore, nonsynonymous SNPs in the C17orf53, LRP4, ADAM19 and IBSP genes were suggestively associated with bone density. Bone mineral density (BMD) is the single best predictor of fragility fractures 1,2 and is used as a reference standard for the description of osteoporosis 3. It is a highly familial quantitative trait, with heritability estimates in the range of 0.6-0.8 (ref. 4), but is also influenced by environmental and medical factors. We 5 and others 6 have recently published reports of genome-wide studies describing several loci for BMD. Both studies yielded a locus on 8q24 harboring the TNFRSF11B (also known as OPG, osteprotegerin) gene. The study by Richards et al. 6 also confirmed the welldocumented LRP5 (low-density lipoprotein receptor-related protein 5) gene 7,8 , whereas we reported loci at the TNFSF11 (also known as RANKL, receptor activator of nuclear factor kB ligand) gene (13q14), the ESR1 (estrogen receptor 1) gene (6q25), the MHC (major histocompatibility complex) region (6p21) and a locus on 1p36 that reached genome-wide significance. We also described additional loci that showed suggestive association but did not reach the genome-wide significance level, including the LRP4 (low-density lipoprotein receptor-related protein 4) gene (11p11), the TNFRSF11A (also known as RANK, receptor activator of the nuclear factor kB) gene and the SP7 (osterix) gene (12q13). We noticed a substantial excess of SNP associations compared to that expected, indicating that true additional association signals might still be found. To search for these additional variants, we expanded the genome-wide scan from 5,861 individuals
Bone, Mar 1, 2010
... involved in prevalence and progression of osteoarthritis HJM Kerkhof, I. Jonsdottir, I. Meule... more ... involved in prevalence and progression of osteoarthritis HJM Kerkhof, I. Jonsdottir, I. Meulenbelt, L. Stolk, AM Valdes, G. Zhai, Y. Zhu, M. Doherty, S. Doherty, A. Tsezou, A. Gonzalez, A. Carr, DT Felson, U. Styrkarsdottir, EP Slagboom, J. Loughlin, F. Rivadeneira, A. Hofman ...