Publications by authors named "William J Devan"

21 Publications

  • Page 1 of 1

Multicystic Dysplastic Kidney With Mass Effect in a Neonate Treated With Nephrectomy: Case Report.

Urology 2021 Mar 10;149:e11-e14. Epub 2020 Dec 10.

Maine Medical Center Division of Neonatal-Perinatal Medicine, Portland, ME.

Multicystic Dysplastic Kidney is a developmental disease that results in a lobulated kidney of noncommunicating cysts and abnormal parenchymal tissue. Dysplastic kidneys are usually benign and often involute over time with conservative management. The second most common cause of palpable abdominal mass in a neonate, Multicystic Dysplastic Kidney can cause respiratory distress secondary to extrinsic compression. However, such cases are sparse. Here we present the case of an otherwise healthy term newborn with an exceptionally large MCDK requiring CPAP support and intubation. His respiratory distress improved immediately after nephrectomy. Communication about cases like this will inform management of future comparable cases.
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http://dx.doi.org/10.1016/j.urology.2020.11.050DOI Listing
March 2021

Unusual cause of Fournier's gangrene: colorectal-genitourinary tract fistulae status post brachytherapy.

BMJ Case Rep 2020 Oct 30;13(10). Epub 2020 Oct 30.

Department of Urology, Maine Medical Center, Portland, Maine, USA.

There are few reports of radiation associated colorectal-genitourinary tract (CRGU) fistulae causing Fournier's gangrene (FG). We describe a case of FG in a patient with possibly two CRGU fistulae in the context of previous high-dose brachytherapy and external beam radiation therapy for prostate cancer. Unfortunately, CRGU fistulae are not well classified as significant risk factors for the development of FG. Our case demonstrates the rationale for maintaining a broad differential in patients presenting with recurrent urinary tract symptoms or necrotising soft tissue infections to include undiagnosed fistulae.
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http://dx.doi.org/10.1136/bcr-2020-235903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604808PMC
October 2020

Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

Stroke 2018 07 18;49(7):1618-1625. Epub 2018 Jun 18.

Massachusetts General Hospital, Boston; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., C.M., K.N.S., G.J.F.).

Background And Purpose: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH.

Methods: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with <5×10 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively.

Results: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; =4.4×10) for lobar ICH volume and an intergenic region overlying numerous copy number variants on (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; =4.3×10) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for (=0.04; meta-analysis =2.5×10; heterogeneity, =0.16) but not for 22q13 (=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; =0.045).

Conclusions: We identified as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.
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http://dx.doi.org/10.1161/STROKEAHA.117.020091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085089PMC
July 2018

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

Neurology 2016 Jan 16;86(2):146-53. Epub 2015 Dec 16.

Authors' affiliations are listed at the end of the article.

Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms.

Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations.

Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)).

Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.
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http://dx.doi.org/10.1212/WNL.0000000000002263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731688PMC
January 2016

Integrative Mouse and Human Studies Implicate ANGPT1 and ZBTB7C as Susceptibility Genes to Ischemic Injury.

Stroke 2015 Dec 5;46(12):3514-22. Epub 2015 Nov 5.

From the Department of Neurosurgery (R.D., J.Z., W.L., N.C., B.Q., J.X., J.W., X.Z., X.W.) and Channing Division of Network Medicine, Department of Medicine (R.D., S.T.W.), Brigham and Women's Hospital, Boston, MA; Department of Neurology, Massachusetts General Hospital, Boston (S.L., W.J.D., V.J.V., J.R., N.R.); Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy (S.L.); Department of Chemical Biology, Northwest Agriculture and Forestry University, Shaanxi, People's Republic of China (W.L., J.W.); Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, People's Republic of China (J.X.); The Jackson Laboratory, Bar Harbor, ME (A.B., B.P.); Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine (A.B.) and Department of Neurosurgery (R.M.F.), University of Pittsburgh School of Medicine, PA; Quinnipiac University Frank H. Netter, MD School of Medicine, Hamden, CT (W.J.D.); University of Massachusetts Medical School, Worcester (V.J.V.); and Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI (K.L.F.).

Background And Purpose: The extent of ischemic injury in response to cerebral ischemia is known to be affected by native vasculature. However, the nonvascular and dynamic vascular responses and their genetic basis are not well understood.

Methods: We performed a genome-wide association study in 235 mice from 33 inbred strains using the middle cerebral artery occlusion model. Population structure and genetic relatedness were accounted for using the efficient mixed-model association method. Human orthologs to the genes associated with the significant and suggestive single-nucleotide polymorphisms from the mouse strain survey were examined in patients with M1 occlusions admitted with signs and symptoms of acute ischemic stroke.

Results: We identified 4 genome-wide significant and suggestive single-nucleotide polymorphisms to be associated with infarct volume in mice (rs3694965, P=2.17×10(-7); rs31924033, P=5.61×10(-6); rs32249495, P=2.08×10(-7); and rs3677406, P=9.56×10(-6)). rs32249495, which corresponds to angiopoietin-1 (ANGPT1), was also significant in the recessive model in humans, whereas rs1944577, which corresponds to ZBTB7C, was nominally significant in both the additive and dominant genetic models in humans. ZBTB7C was shown to be upregulated in endothelial cells using both in vitro and in vivo models of ischemia.

Conclusions: Genetic variations of ANGPT1 and ZBTB7C are associated with increased infarct size in both mice and humans. ZBTB7C may modulate the ischemic response via neuronal apoptosis and dynamic collateralization and, in addition to ANGPT1, may serve as potential novel targets for treatments of cerebral ischemia.
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http://dx.doi.org/10.1161/STROKEAHA.115.010767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704955PMC
December 2015

Rare Coding Variation and Risk of Intracerebral Hemorrhage.

Stroke 2015 Aug 25;46(8):2299-301. Epub 2015 Jun 25.

From the Center for Human Genetic Research (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.), J. Philip Kistler Stroke Research Center (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., A.M.A., M.R.R., K.S., A.V., S.M.G., J.R.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.); Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC (D.M., W.M.B., C.D.L.); Quinnipiac University, Frank H. Netter MD School of Medicine, Hamden, CT (W.J.D.); Department of Environmental Health (G.S., R.D.) and Department of Neurology and Rehabilitation (D.W.), University of Cincinnati College of Medicine, OH; Department of Neurology, Harborview Medical Center, University of Washington, Seattle (D.L.T.); Department of Neurology, University of Florida College of Medicine, Jacksonville (S.L.S.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.S.); Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Department of Neurology, University of Michigan Health System, Ann Arbor (D.L.B.); and Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville (B.B.W.).

Background And Purpose: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage.

Methods: A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed.

Results: No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing.

Conclusions: Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects.
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http://dx.doi.org/10.1161/STROKEAHA.115.009838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519408PMC
August 2015

Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.

Neurology 2015 Mar 4;84(9):918-26. Epub 2015 Feb 4.

Authors' affiliations are listed at the end of the article.

Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
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http://dx.doi.org/10.1212/WNL.0000000000001309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667PMC
March 2015

APOE ε variants increase risk of warfarin-related intracerebral hemorrhage.

Neurology 2014 Sep 22;83(13):1139-46. Epub 2014 Aug 22.

From the Center for Human Genetic Research (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., V.V., M.R.R., L.P.C., A.M.A., K.S., A.V., S.M.G., A.B., J.R., C.D.A.), J. Philip Kistler Stroke Research Center (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., V.V., M.R.R., A.B., J.R., C.D.A.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., M.R.R., A.B., J.R., C.D.A.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., M.R.R., A.B., J.R., C.D.A.), Broad Institute, Cambridge, MA; Department of Epidemiology (G.J.F., P.K.), Harvard School of Public Health, Boston; Department of Neurology (M.S.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology (J.F.M.), Mayo Clinic, Jacksonville, FL; Stroke Program (D.L.B.), Department of Neurology, University of Michigan Health System, Ann Arbor; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia Health System, Charlottesville; Department of Neurology (S.L.S.), University of Florida College of Medicine, Jacksonville; Stroke Center (D.L.T.), Harborview Medical Center, University of Washington, Seattle; and University of Cincinnati College of Medicine (M.L.F., S.R.M., R.D., D.W.), OH.

Objective: We aimed to assess the effect of APOE ε variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH.

Methods: This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE ε variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE ε and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE ε and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power.

Results: The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE ε2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas ε4 was associated with lobar (OR 2.09; p < 0.001) but not nonlobar wICH (p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with ε2 (p = 0.03) and ε4 (p = 0.003) for lobar but not for nonlobar wICH (p > 0.20). Genotyping information on APOE ε variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found (p > 0.20).

Conclusions: APOE ε variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted.
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http://dx.doi.org/10.1212/WNL.0000000000000816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176027PMC
September 2014

A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach.

PLoS Genet 2014 Jul 31;10(7):e1004469. Epub 2014 Jul 31.

Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Center for Non-Communicable Diseases, Karachi, Pakistan.

Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
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http://dx.doi.org/10.1371/journal.pgen.1004469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117446PMC
July 2014

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.

Neurology 2014 Aug 16;83(8):678-85. Epub 2014 Jul 16.

Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
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http://dx.doi.org/10.1212/WNL.0000000000000707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150131PMC
August 2014

Dopamine genetic risk score predicts depressive symptoms in healthy adults and adults with depression.

PLoS One 2014 16;9(5):e93772. Epub 2014 May 16.

Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America; Department of Neurology, University of California Irvine, Irvine, California, United States of America.

Background: Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression.

Methods: Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3).

Results: In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = -0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = -0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = -0.86, p = 0.15).

Conclusions: Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093772PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023941PMC
January 2015

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Am J Hum Genet 2014 Apr 20;94(4):511-21. Epub 2014 Mar 20.

Department of Neurology, Medical University of Graz, Graz 8036, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
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http://dx.doi.org/10.1016/j.ajhg.2014.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980413PMC
April 2014

Accuracy of imputation to infer unobserved APOE epsilon alleles in genome-wide genotyping data.

Eur J Hum Genet 2014 Oct 22;22(10):1239-42. Epub 2014 Jan 22.

1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA [2] Department of Neurology, J Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA [3] Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.

Apolipoprotein E, encoded by APOE, is the main apoprotein for catabolism of chylomicrons and very low density lipoprotein. Two common single-nucleotide polymorphisms (SNPs) in APOE, rs429358 and rs7412, determine the three epsilon alleles that are established genetic risk factors for late-onset Alzheimer's disease (AD), cerebral amyloid angiopathy, and intracerebral hemorrhage (ICH). These two SNPs are not present in most commercially available genome-wide genotyping arrays and cannot be inferred through imputation using HapMap reference panels. Therefore, these SNPs are often separately genotyped. Introduction of reference panels compiled from the 1000 Genomes project has made imputation of these variants possible. We compared the directly genotyped and imputed SNPs that define the APOE epsilon alleles to determine the accuracy of imputation for inference of unobserved epsilon alleles. We utilized genome-wide genotype data obtained from two cohorts of ICH and AD constituting subjects of European ancestry. Our data suggest that imputation is highly accurate, yields an acceptable proportion of missing data that is non-differentially distributed across case and control groups, and generates comparable results to genotyped data for hypothesis testing. Further, we explored the effect of imputation algorithm parameters and demonstrated that customization of these parameters yields an improved balance between accuracy and missing data for inferred genotypes.
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http://dx.doi.org/10.1038/ejhg.2013.308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169533PMC
October 2014

Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.

Stroke 2014 Feb 16;45(2):394-402. Epub 2014 Jan 16.

From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom (S.B., H.S.M.); Laboratory of Neurogenetics (M.A.N.) and Laboratory of Epidemiology and Population Sciences (L.J.L.), National Institute on Aging, National Institutes of Health, Bethesda, MD; Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health (E.G.H.) and Center for Translational Neuroscience and Mental Health Research (C.L.), University of Newcastle, Callaghan, NSW, Australia; Center for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton, NSW, Australia (E.G.H.); Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA (W.J.D., J.R.); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (Y.-C.C., B.D.M.); Department of Veterans Affairs and Veterans Affairs Medical Center, Baltimore Geriatric Research, Education, and Clinical Center (GRECC), Baltimore, MD (Y.-C.C., B.D.M.); Department of Epidemiology (C.A.I.-V., B.F.J.V., M.A.I., C.M.v.D.), Department of Neurology (C.A.I.-V., M.A.I.), and Department of Radiology (B.F.J.V., M.A.I.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Cardiovascular Health Research Unit (J.C.B., B.M.P.), Department of Medicine (J.C.B., B.M.P.), Department of Epidemiology (B.M.P.), and Department of Health Services (B.M.P.), University of Washington, Seattle, WA; Institute for Molecular Medicine (A.Y.J., M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center at Houston; Department of Neurology, Boston University School of Medicine, Boston, MA (A.L.d.S., S.S.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (A.L.d.S.); The National Heart, Lung and

Background And Purpose: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

Methods: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

Results: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

Conclusions: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
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http://dx.doi.org/10.1161/STROKEAHA.113.002938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006951PMC
February 2014

Heritability estimates identify a substantial genetic contribution to risk and outcome of intracerebral hemorrhage.

Stroke 2013 Jun 4;44(6):1578-83. Epub 2013 Apr 4.

Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St, CPZN-6818, Boston, MA 02114, USA.

Background And Purpose: Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome.

Methods: We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality.

Results: ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOEloci and at 12% (SE, 4%) for APOE.

Conclusions: Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.
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http://dx.doi.org/10.1161/STROKEAHA.111.000089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684199PMC
June 2013

Common variants within oxidative phosphorylation genes influence risk of ischemic stroke and intracerebral hemorrhage.

Stroke 2013 Mar 29;44(3):612-9. Epub 2013 Jan 29.

Massachusetts General Hospital, Boston, MA 02114, USA.

Background And Purpose: Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH).

Methods: This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts.

Results: IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008).

Conclusions: This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences.
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http://dx.doi.org/10.1161/STROKEAHA.112.672089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582722PMC
March 2013

Burden of blood pressure-related alleles is associated with larger hematoma volume and worse outcome in intracerebral hemorrhage.

Stroke 2013 Feb 15;44(2):321-6. Epub 2013 Jan 15.

Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St, CPZN-6818, Boston, MA 02114, USA.

Background And Purpose: Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease seems to influence not only risk of ICH but also the size of the hematoma. As the burden of high blood pressure-related alleles is associated with both hypertension-related end-organ damage and risk of ICH, we sought to determine whether this burden influences ICH baseline hematoma volume.

Methods: Prospective study in subjects of European descent with supratentorial ICH who underwent genome-wide genotyping. Forty-two single nucleotide polymorphisms associated with high blood pressure were identified from a publicly available database. A genetic risk score was constructed based on these single nucleotide polymorphisms. The score was used as the independent variable in univariate and multivariate regression models for admission ICH volume and poor clinical outcome (modified Rankin Scale, 3-6).

Results: A total of 323 ICH cases were enrolled in the study (135 deep and 188 lobar intracranial hematomas). The blood pressure-based genetic risk score was associated with both baseline hematoma volume and poor clinical outcome specifically in deep ICH. In multivariate regression analyses, each additional SD of the score increased mean deep ICH volume by 28% (or 2.7 mL increase; β=0.28; SE=0.11; P=0.009) and risk of poor clinical outcome by 71% (odds ratio, 1.71; 95% confidence interval, 1.05-2.80; P=0.03).

Conclusions: Increasing numbers of high blood pressure-related alleles are associated with mean baseline hematoma volume and poor clinical outcome in ICH. These findings suggest that the small vessel vasculopathy responsible for the occurrence of the hemorrhage also influences its volume.
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http://dx.doi.org/10.1161/STROKEAHA.112.675181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560332PMC
February 2013

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.

Nat Genet 2012 Oct 2;44(10):1147-51. Epub 2012 Sep 2.

Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
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http://dx.doi.org/10.1038/ng.2397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651583PMC
October 2012

Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage.

Stroke 2012 Nov 28;43(11):2877-83. Epub 2012 Aug 28.

Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, and Department of Epidemiology, Harvard School of Public Health, 185 Cambridge Street; CPZN-6818, Boston, MA 02114, USA.

Background And Purpose: Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN.

Methods: We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables.

Results: No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score.

Conclusions: Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.
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http://dx.doi.org/10.1161/STROKEAHA.112.659755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479325PMC
November 2012

TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer's Disease.

Transl Stroke Res 2012 Jul 12;3(Suppl 1):102-12. Epub 2012 Apr 12.

Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Cerebral amyloid angiopathy (CAA) related intracerebral hemorrhage (ICH) is a devastating form of stroke with no known therapies. Clinical, neuropathological, and genetic studies have suggested both overlap and divergence between the pathogenesis of CAA and the biologically related condition of Alzheimer's disease (AD). Among the genetic loci associated with AD are APOE and TOMM40, a gene in close proximity to APOE. We investigate here whether variants within TOMM40 are associated with CAA-related ICH and CAA neuropathology. Using cohorts from the Massachusetts General Hospital (MGH) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), we designed a comparative analysis of high-density SNP genotype data for CAA-related ICH and AD. APOE ε4 was associated with CAA-related ICH and AD, while APOE ε2 was protective in AD but a risk factor for CAA. A total of 14 SNPs within TOMM40 were associated with AD (p < 0.05 after multiple testing correction), but not CAA-related ICH (all p > 0.20); as a result, all AD-associated SNPs within TOMM40 showed heterogeneity of effect in CAA-related ICH (BD p < 0.001). Analysis of CAA neuropathology in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), however, found that neuritic plaque, diffuse plaque burden, and vascular amyloid burden associated with all TOMM40 SNPs (p < 0.02). These results suggest that alterations in TOMM40 can promote vascular as well as plaque amyloid deposition, but not the full pathogenic pathway leading to CAA-related ICH.
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http://dx.doi.org/10.1007/s12975-012-0161-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054941PMC
July 2012

Statin treatment and functional outcome after ischemic stroke: case-control and meta-analysis.

Stroke 2011 May 17;42(5):1314-9. Epub 2011 Mar 17.

J. Philip Kistler Stroke Research Center, Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital, 175 Cambridge Street, Suite 300, Boston MA 02114, USA.

Background And Purpose: Multiple studies suggest that statin use before acute ischemic stroke is associated with improved functional outcome. However, available evidence is conflicting, and several published reports are limited by small sample sizes. We therefore investigated the effect of antecedent use of statins on stroke outcome by performing a meta-analysis of all results from published studies as well as our own unpublished data.

Methods: We performed a systematic literature search and meta-analysis of studies investigating the association between prestroke statin use and clinical outcome and included additional data from 126 prestroke statin users and 767 nonusers enrolled at our institution. A total of 12 studies, comprising 2013 statin users and 9682 nonusers, was meta-analyzed using a random effects model. We also meta-analyzed results for individual Trial of ORG 10172 in Acute Stroke Treatment stroke subtypes to determine whether the effect of statin use differed across subtypes using the Breslow-Day test.

Results: Meta-analysis of all available data identified an association between prestroke statin use and improved functional outcome (OR, 1.62; 95% CI, 1.39 to 1.88), but we uncovered evidence of publication bias. The effect of statin use on functional outcome was found to be larger for small vessel strokes compared with other subtypes (Breslow-Day P=0.008).

Conclusions: Antecedent use of statins is associated with improved outcome in patients with acute ischemic stroke. This association appears to be stronger in patients with small vessel stroke subtype. However, evidence of publication bias in the existing literature suggests these findings should be interpreted with caution.
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http://dx.doi.org/10.1161/STROKEAHA.110.605923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093764PMC
May 2011
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