Publications by authors named "Vilmundur G Gudnason"

5 Publications

  • Page 1 of 1

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

Background And Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.

Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.

Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.

Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Stroke 2018 08;49(8):1812-1819

Department of Biochemistry (D.W.B., N.D.P.), Wake Forest School of Medicine, Winston-Salem, NC.

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P=4.5×10) partially independent of known common signal ( P=1.4×10). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P=1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P=2.8×10). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
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http://dx.doi.org/10.1161/STROKEAHA.118.020689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202149PMC
August 2018

Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: the AGES-Reykjavik longitudinal study.

J Bone Miner Res 2013 Oct;28(10):2165-76

Faculty of Industrial Engineering, Mechanical Engineering and Computer Science, University of Iceland, Reykjavik, Iceland.

The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density (BMD), to investigate changes in regional cortical thickness, as well as cortical and trabecular BMD at the mid-femoral neck. Segmental quantitative computed tomography (QCT) analysis was used to assess bone measurements in two anatomic subregions, the superolateral (superior) and inferomedial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66-90 years) who were participants in the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 years (mean baseline age 74 years). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical volumetric bone mineral density (vBMD) inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck dual-energy X-ray absorptiometry (DXA)-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men.
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http://dx.doi.org/10.1002/jbmr.1960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779495PMC
October 2013

Mid-thigh cortical bone structural parameters, muscle mass and strength, and association with lower limb fractures in older men and women (AGES-Reykjavik Study).

Calcif Tissue Int 2012 May 27;90(5):354-64. Epub 2012 Mar 27.

University of Iceland, Reykjavik, Iceland.

In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained <10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns.
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http://dx.doi.org/10.1007/s00223-012-9585-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111551PMC
May 2012

Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study.

Bone 2011 Jun 5;48(6):1268-76. Epub 2011 Apr 5.

University of Iceland, Reykjavik, Iceland.

In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm², DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture.
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http://dx.doi.org/10.1016/j.bone.2011.03.776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129599PMC
June 2011