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  • Fornage, Myriam  (22)
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  • 1
    In: Stroke, 2014, Vol.45(2), pp.403-412
    Description: BACKGROUND AND PURPOSE—: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. METHODS—: The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case–control study of ischemic stroke. RESULTS—: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10; ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P〈10). CONCLUSIONS—: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
    Keywords: Genetic Epidemiology ; Risk Factors ; Stroke;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 2
    In: Stroke, 2018, Vol.49(8), pp.1812-1819
    Description: 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; PEA=4.5×10) partially independent of known common signal (PEA(conditional)=1.4×10). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=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 (Prs34136221=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.
    Keywords: Cerebral Small Vessel Disease ; Exome ; Magnetic Resonance Imaging ; Meta-Analysis ; White Matter ; Brain -- Diagnostic Imaging ; Exome -- Genetics ; Genetic Variation -- Genetics ; Magnetic Resonance Imaging -- Methods ; Mitochondrial Proteins -- Genetics ; White Matter -- Diagnostic Imaging;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 3
    Language: English
    In: Annals of Neurology, June 2011, Vol.69(6), pp.928-939
    Description: OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
    Keywords: Medicine;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 4
    In: Stroke, 2010, Vol.41(2), pp.210-217
    Description: BACKGROUND AND PURPOSE—: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS—: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had ≥1 MRI infarct). RESULTS—: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68–0.84; P=4.64×10). Highly suggestive associations (P〈1.0×10) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r〉0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. CONCLUSIONS—: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
    Keywords: Medicine;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 5
    Language: English
    In: Biological Psychiatry, 15 April 2015, Vol.77(8), pp.749-763
    Description: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations ( 〈 5 × 10 ) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. rs4420638, near , was associated with poorer delayed recall performance in discovery ( = 5.57 × 10 ) and replication cohorts ( = 5.65 × 10 ). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [ ] = 3.11 × 10 , and rs6813517 [ ], = 2.58 × 10 ) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with and , both related to ubiquitin metabolism. This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
    Keywords: Alzheimer Disease ; Dementia ; Epidemiology ; Genetics ; Population-Based ; Verbal Declarative Memory ; Medicine ; Biology ; Chemistry
    ISSN: 0006-3223
    E-ISSN: 1873-2402
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  • 6
    Language: English
    In: The American Journal of Human Genetics, 05 September 2013, Vol.93(3), pp.545-554
    Description: High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci ( - , , , , and ) reached genome-wide significance (p 〈 1.0 × 10 ) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci ( , , and ) lack previous associations with BP. We also identified one independent signal in a known BP locus ( ) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 7
    Description: Stroke has multiple etiologies but the underlying genes and pathways are largely unknown. We conducted a multi-ancestry genome-wide association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 novel stroke risk loci bringing the total to 32. We further found shared genetic variation with related vascular traits including blood pressure, cardiac traits, and venous thromboembolism at individual loci (N=18), and using genetic risk scores and LD score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven novel loci point to mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy....
    Keywords: Afgen Consortium ; Cohorts For Heart And Aging Research In Genomic Epidemiology (Charge) Consortium ; International Genomics Of Blood Pressure (Igen-Bp) Consortium ; Invent Consortium ; Starnet ; Biobank Japan Cooperative Hospital Group ; Compass Consortium ; Epic-Cvd Consortium ; Epic-Interact Consortium ; International Stroke Genetics Consortium (Isgc) ; Metastroke Consortium ; Neurology Working Group Of The Charge Consortium ; Ninds Stroke Genetics Network (Sign) ; Uk Young Lacunar Dna Study ; Megastroke Consortium ; Megastroke Consortium:
    ISSN: 1061-4036
    Source: DataCite
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  • 8
    Language: English
    In: Nature genetics, April 2018, Vol.50(4), pp.524-537
    Description: Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
    Keywords: Stroke -- Genetics
    ISBN: 4158801800583
    ISSN: 19326203
    E-ISSN: 1546-1718
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  • 9
    Language: English
    In: The American Journal of Human Genetics, 06 February 2014, Vol.94(2), pp.233-245
    Description: Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (〉98 or 〈2 percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in , encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in , and , three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 10
    In: Circulation: Cardiovascular Genetics, 2015, Vol.8(2), pp.398-409
    Description: BACKGROUND—: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. METHODS AND RESULTS—: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10) and identified novel loci on chr10q24 (P=1.6×10) and chr2p21 (P=4.4×10). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10) and chr2p16 (P=1.5×10). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). CONCLUSIONS—: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
    Keywords: Medicine;
    ISSN: 1942-325X
    E-ISSN: 19423268
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