2012

DOI: 10.1038/ng.2397

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

Elizabeth G. Holliday¹,

Jane Maguire²,

Tiffany‐Jane Evans³

et al.

Abstract: 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 signifi… Show more

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Small-vessel Disease (Lacunar Stroke)2

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Cited by 153 publications

(111 citation statements)

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“…13,14,[35][36][37] Importantly, in the largest meta-analysis to date, all associations were with ischaemic stroke subtypes, and these showed much stronger association than in an analysis with all ischaemic stroke (κ = 1.24, 1.23, 1.19, and 1.11 for rs2107595 (HDAC9), rs6843082 (PITX2), rs879324 (ZFHX3), and rs2383207 (9p21), respectively). 13 Further to this, analyses of early onset cases suggest even stronger associations with young onset cases at these loci.…”

Section: Discussionmentioning

confidence: 99%

Homogeneous case subgroups increase power in genetic association studies

¹

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²

,

³

2014

Eur J Hum Genet

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Genome-wide association studies of clinically defined cases against controls have transformed our understanding of the genetic causes of many diseases. However, there are limitations to the simple clinical definitions used in these studies, and GWAS analyses are beginning to explore more refined phenotypes in subgroups of the existing data sets. These analyses are often performed ad hoc without considering the power requirements to justify such analyses. Here we derive expressions for the relative power of such subgroup analyses and determine the genotypic relative risks (GRRs) required to achieve equivalent power to a full analysis for relevant scenarios. We show that only modest increases in GRRs may be required to offset the reduction in power from analysing fewer cases, implying that analyses of more genetically homogenous case subgroups may have the potential to identify further associations. We find that, for lower genotypic relative risks in the full sample, subgroup analyses of more homogeneous cases have relatively more power than for higher index genotypic relative risks and that this effect is stronger for rare as opposed to common variants. As GWA studies are likely to have now identified the majority of SNPs with stronger effects, these results strongly advocate a renewed effort to identify phenotypically homogeneous disease groups, in which power to detect genetic variants with small effects will be greater. These results suggest that analysis of case subsets could be a powerful strategy to uncover some of the hidden heritability for common complex disorders, particularly in identifying rarer variants of modest effect.

“…13,14,[35][36][37] Importantly, in the largest meta-analysis to date, all associations were with ischaemic stroke subtypes, and these showed much stronger association than in an analysis with all ischaemic stroke (κ = 1.24, 1.23, 1.19, and 1.11 for rs2107595 (HDAC9), rs6843082 (PITX2), rs879324 (ZFHX3), and rs2383207 (9p21), respectively). 13 Further to this, analyses of early onset cases suggest even stronger associations with young onset cases at these loci.…”

Section: Discussionmentioning

confidence: 99%

Homogeneous case subgroups increase power in genetic association studies

¹

,

²

,

³

2014

Eur J Hum Genet

Self Cite

View full text Add to dashboard Cite

Genome-wide association studies of clinically defined cases against controls have transformed our understanding of the genetic causes of many diseases. However, there are limitations to the simple clinical definitions used in these studies, and GWAS analyses are beginning to explore more refined phenotypes in subgroups of the existing data sets. These analyses are often performed ad hoc without considering the power requirements to justify such analyses. Here we derive expressions for the relative power of such subgroup analyses and determine the genotypic relative risks (GRRs) required to achieve equivalent power to a full analysis for relevant scenarios. We show that only modest increases in GRRs may be required to offset the reduction in power from analysing fewer cases, implying that analyses of more genetically homogenous case subgroups may have the potential to identify further associations. We find that, for lower genotypic relative risks in the full sample, subgroup analyses of more homogeneous cases have relatively more power than for higher index genotypic relative risks and that this effect is stronger for rare as opposed to common variants. As GWA studies are likely to have now identified the majority of SNPs with stronger effects, these results strongly advocate a renewed effort to identify phenotypically homogeneous disease groups, in which power to detect genetic variants with small effects will be greater. These results suggest that analysis of case subsets could be a powerful strategy to uncover some of the hidden heritability for common complex disorders, particularly in identifying rarer variants of modest effect.

“…23 An ageof-onset analysis that was weighted towards younger age at stroke onset found a specific association of large-artery atherosclerotic stroke with a variant in the MMP12 gene, which encodes macrophage metalloelastase, also known as matrix metalloproteinase 12. 24 This observation was supported by a study that showed increased levels of MMP12 mRNA in the atherosclerotic carotid plaque compared with normal arterial wall tissue.…”

Section: Small-vessel Disease (Lacunar Stroke)mentioning

confidence: 99%

“…A GWAS conducted in a group of Japanese patients with ischaemic stroke identified a genetic variant in PRKCH. 23 This gene encodes a serine-threonine kinase that regulates a variety of cellular functions including proliferation, differentiation and apoptosis. The variant identified was specifically associated with small-vessel stroke, a result that was replicated in both an independent Japanese cohort and a Chinese population.…”

Section: Small-vessel Disease (Lacunar Stroke)mentioning

confidence: 99%

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

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,

²

2014

Nat Rev Neurol

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| The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings.

“…1 Thanks to genome-wide association studies (GWAS), genetics of complex diseases has made dramatic steps forward in the last few years 2 but very few single-nucleotide polymorphisms (SNPs) have been invariantly associated with ischemic stroke. [3][4][5][6][7] Moreover, the relative risk conferred by individual genetic variants is usually low. Thus, in an attempt to estimate the aggregate effect of several gene variants, different genetic risk scores (GRS) have been constructed including a few studies on stroke with inconsistent results.…”

Section: Introductionmentioning

confidence: 99%

A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case–control study

¹

,

²

,

³

et al. 2014

Eur J Hum Genet

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Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P = 0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P = 0.25), MDC (1.168 (1.060-1.288); P = 0.002) and SAHLSIS (1.124 (0.997-1.267); P = 0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension. INTRODUCTIONStroke is one of the leading causes of mortality, morbidity and disability worldwide. 1 Thanks to genome-wide association studies (GWAS), genetics of complex diseases has made dramatic steps forward in the last few years 2 but very few single-nucleotide polymorphisms (SNPs) have been invariantly associated with ischemic stroke. [3][4][5][6][7] Moreover, the relative risk conferred by individual genetic variants is usually low. Thus, in an attempt to estimate the aggregate effect of several gene variants, different genetic risk scores (GRS) have been constructed including a few studies on stroke with inconsistent results. [8][9][10][11][12][13][14][15] Interestingly, the selection of the SNPs to be included in GRS calculation have been based on different criteria: SNPs detected by GWAS either associated or not associated with known cardiovascular risk factors, as well as SNPs in candidate genes or pathways. [8][9][10][11][12][13][14][15] High blood pressure (BP) is the major risk factors for stroke and among the most important ones for other cardiovascular events. 16,17 Despite BP and hypertension being heritable traits, 18 the search for genetic variants associated with these traits has been more challenging compared with other cardiovascular risk factors. Only in recent years, GWAS have discovered several genetic variants which associate with BP-related ...

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