Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Bellenguez, Céline; Bevan, Steve; Gschwendtner, Andreas; Cca., Spencer; Burgess, A I; Pirinen, Matti; Jackson, Caroline; Traylor, Matthew; Strange, Amy; Su, Zhan; Syme, Paul D.; Malik, Rainer; Pera, Joanna; Niu, Bo; Lemmens, Robin; Freeman, Colin; Schanz, Renata; James, Thomas N.; Poole, D L; Murphy, Lee; Segal, Helen; Cortellini, Lynelle; Cheng, Yuehua; Woo, Daniel; Nalls, Michael A.; Müller‐Myhsok, Bertram; Meisinger, Christa; Seedorf, Udo; Ross-Adams, Helen; Boonen, Steven; Wloch-Kopec, Dorota; Valant, Valerie; Slark, Julia; Furie, Karen L.; Delavaran, Hossein; Langford, Cordelia; Deloukas, Panos; Edkins, Sarah; Hunt, Sarah; Gray, Emma; Dronov, Serge; Peltonen, Leena; Grétarsdóttir, Sólveig; Þorleifsson, Guðmar; Þorsteinsdóttir, Unnur; Stefánsson, Kāri; Boncoraglio, Giorgio B.; Parati, Eugenio; Attia, John; Holliday, Elizabeth G.; Levi, Christopher; Mg, Franzosi; Goel, Anuj; Helgadóttir, Anna; Blackwell, J. M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Duncanson, Audrey; Jankowski, Janusz; Mathew, Christopher G.; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, S. J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Worrall, Bradford B.; Kittner, Steven J.; Mitchell, Braxton D.; Kissela, Brett M.; Meschia, James F.; Thijs, Vincent; Lindgren, Arne; MacLeod, Mary Joan; Słowik, Agnieszka; Walters, James; Rosand, Jonathan; Sharma, Pankaj; Farrall, Martin; Sudlow, Cathie; Rothwell, Peter M.; Dichgans, Martin; Donnelly, Peter; Markus, Hugh S.

doi:10.1038/ng.1081

Cited by 373 publications

(274 citation statements)

References 30 publications

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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: 91%

“…Second, such clinical diagnoses ignore underlying heterogeneity in disease pathogenesis where case subtyping might be more appropriate. Examples of diseases with genetically distinct subgroups include ischaemic stroke, where at least three distinct pathologies (cardioembolic, small vessel and large vessel) lead to stroke events; 13,14 migraine, where cases with or without aura have distinct genetic susceptibility factors; 15 and rheumatoid arthritis, where anti-citrullinated peptide antibody-negative individuals show distinct genetic associations, particularly in the HLA region. 16,17 Third, heterogeneity in genetic susceptibility to disease may exist.…”

Section: Introductionmentioning

confidence: 99%

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Homogeneous case subgroups increase power in genetic association studies

2014

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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.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Homogeneous case subgroups increase power in genetic association studies

2014

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“…49 Moreover, a recent genome-wide association study found two single nucleotide polymorphic (SNP) variants of HDAC9 to be strongly linked to large blood vessel disease in humans. 50 These findings raise the intriguing possibility that therapeutically targeting HDAC9 in obesity could also favorably modulate the development of cardiovascular complications, a major cause of morbidity and mortality in this population.…”

Section: Hdac9 As a Potential Therapeutic Target In Obesity: Present mentioning

confidence: 99%

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

et al. 2014

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“…SNP data for these samples were available from a recent genome-wide association study using the Affymetrix SNP Array 6.0 as previously described (Bellenguez et al 2012).…”

Section: Genotypingmentioning

confidence: 99%

The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis

et al. 2013

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Background. Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients.Method. In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability.Results. Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1-3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis.Conclusions. These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.

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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Cited by 373 publications

References 30 publications

Homogeneous case subgroups increase power in genetic association studies

Homogeneous case subgroups increase power in genetic association studies

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis

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