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Genome wide association study on coronary heart disease in patients with familial hypercholesterolemia

ABSTRACT: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap 550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (p<1×10-4). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an ‘extreme genetics’ approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may therefore not lead to significant gains in statistical power. (NB submitten and conditionally accepted at European Journal of Human Genetics-please use abstract only for internal review until submission complete)

PROVIDER: EGAS00001000734 | EGA |

REPOSITORIES: EGA

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Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Versmissen Jorie J Oosterveer Daniëlla M DM Yazdanpanah Mojgan M Dehghan Abbas A Hólm Hilma H Erdman Jeanette J Aulchenko Yurii S YS Thorleifsson Gudmar G Schunkert Heribert H Huijgen Roeland R Vongpromek Ranitha R Uitterlinden André G AG Defesche Joep C JC van Duijn Cornelia M CM Mulder Monique M Dadd Tony T Karlsson Hróbjartur D HD Ordovas Jose J Kindt Iris I Jarman Amelia A Hofman Albert A van Vark-van der Zee Leonie L Blommesteijn-Touw Adriana C AC Kwekkeboom Jaap J Liem Anho H AH van der Ouderaa Frans J FJ Calandra Sebastiano S Bertolini Stefano S Averna Maurizio M Langslet Gisle G Ose Leiv L Ros Emilio E Almagro Fátima F de Leeuw Peter W PW Civeira Fernando F Masana Luis L Pintó Xavier X Simoons Maarten L ML Schinkel Arend F L AF Green Martin R MR Zwinderman Aeilko H AH Johnson Keith J KJ Schaefer Arne A Neil Andrew A Witteman Jacqueline C M JC Humphries Steve E SE Kastelein John J P JJ Sijbrands Eric J G EJ

European journal of human genetics : EJHG 20140611 3

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. ...[more]

PMID: 24916650

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Project description:Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis was used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal and femoral BMD revealed four significant associations (-log10P > 5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12 and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism though which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression gene module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cell of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits. RNA from cortical bone (femoral diaphysis free of marrow) were profiled from 99 Hybrid Mouse Diversity Panel strains were profiled. Sixteen-week old male mice were used in this study. A total of 1-3 mice per strain were arrayed.

Dataset Information

Genome wide association study on coronary heart disease in patients with familial hypercholesterolemia

Publications

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

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