EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD00010000578249EGA dataset EGAD00010000578EGAMutations 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 HumanHap550K 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.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"Fredrickson type IIa hyperlipoproteinemia" EXACT [MTHICD9_2006:272.0], Familial Defective, Disorders, LDL Receptor Disorder, Type IIa, Essential Hypercholesterolemia, Hyper-beta-Lipoproteinemias, Receptor Disorders, Coronary Diseases, Heart Diseases, Autosomal Dominant Hypercholesterolemia, Coronary, Familial Ligand Defective, Dominant Hypercholesterolemias, Hyperbetalipoproteinemia, Relative, Xanthomatoses, "type II hyperlipidemia" EXACT [NCI2004_11_17:C34704], Lipoproteinemias, Heart Disease, Hyper-Low, Hypercholesterolemia, Type IIa Hyperlipoproteinemias, Essential Hypercholesterolemias, Coronary Heart, "Fredrickson type IIa lipidaemia" EXACT [SNOMEDCT_2005_07_31:190772003], type II hyperlipidemia, Hyperlipoproteinemia Type IIb, Hyperlipoproteinemia Type IIa, "familial hypercholesteremia" EXACT [CSP2005:1849-4634], Apolipoprotein B-100, Hyperlipoproteinemia, Familial Hypercholesterolemic Xanthomatoses, Combined Hyperlipoproteinemia, Hypercholesterolemias, Familial Combined, Hyperlipoproteinemias, Hyper-Low Density Lipoproteinemias, Familial, Hyperlipoproteinemia Type IIs, genetic, Autosomal Dominant Hypercholesterolemias, Hyper-Low Density Lipoproteinemia, "familial hyperbetalipoproteinaemia" EXACT [SNOMEDCT_2005_07_31:190776000], Type II Hyperlipoproteinemia, Disorder, Dominant Hypercholesterolemia, Hypercholesterolemic Xanthomatosis, Hyper-Low-Density-Lipoproteinemias, Hyper-Low-Density-Lipoproteinemia, LDL Receptor Disorders, constitutitional genetic, Autosomal, heredity., Disease, "familial hypercholesterolemia (disorder)" EXACT [SNOMEDCT_2005_07_31:398036000], Apolipoprotein B 100, Coronary Heart Disease, coronary arteriosclerosis, Familial Hypercholesterolemias, Density Lipoproteinemia, Coronary Heart Diseases, Essential, Hypercholesterolemic Xanthomatoses, familial, Hyperbetalipoproteinemias, "familial hypercholesterolemia (disorder)" EXACT [SNOMEDCT_2005_07_31:31654005], Familial Combined Hyperlipoproteinemia, Hyper-Low Density, Hyperlipoproteinemia Type IIas, Xanthomatosis, Familial Combined Hyperlipoproteinemias, LDL Receptor, Relative Risks, Diseases, Hyperlipoproteinemia Type 2, Relative Risk, Receptor Disorder, Autosomal Dominant, "Fredrickson type IIa hyperlipoproteinemia (disorder)" EXACT [SNOMEDCT_2005_07_31:397915002], FH, Type II Hyperlipoproteinemias, Type B, Risk, Hyperlipoproteinemia Type 2s, "familial hyperbetalipoproteinaemia" EXACT [SNOMEDCT_2005_07_31:389985001], Lipoproteinemia, "hyperbetalipoproteinemia (disorder)" EXACT [SNOMEDCT_2005_07_31:190773008], Risks, Type IIa Hyperlipoproteinemia, LDL, Familial Hypercholesterolemic, Type 2, Familial Hypercholesterolemia, Hyper beta Lipoproteinemia, Combined Hyperlipoproteinemias, Hyper Low Density Lipoproteinemia, Familial Ligand-Defective, "familial hyperbetalipoproteinaemia" EXACT [SNOMEDCT_2005_07_31:190775001], inherited genetic, Familial Hypercholesterolemic Xanthomatosis, Type II, hereditary, Density Lipoproteinemias, Hyper-beta-Lipoproteinemia, Hyperlipoproteinemia Type IIbsl(1)Ab, DmelCG9414, DE Cadh, AU018859, fs(1)M34, E-Cadherin, csp2, 3.-.-.-, l(2)10469, l(2)k03401, drep4, cold antibody disease, CG4601, Caspase-activated nuclease, CadE, 5730477D02Rik, Ecad, CPAN, 4.1.1.6, DHO, cadh, DCAD2, DCad2, DmelCG1759, Cpad, CG18572, cold antibody, S67, Immune-responsive gene 1 protein, DECad, CG3722, DFF40, fs(1)829, ECAD, ECad, cd, DE Cad, 2410008J01Rik, DE-CAD2, dEcad, D-cad, 38E.19, DmelCG18572, Rep4, ACT, DECadh, DEcad, CADH, DE[cyto], DE, coronary arteriosclerosis, anon-WO2004063362.83, CPS, Drep4, cold antibody hemolytic anemia, DREP-4, DE-cad, Shg, Caspase-activated DNase, DE-Cad2, collisionally activated dissociation, Cadh, CID, DE-cadh, N-cad, CAD, Cad, Su(b), ECadh, DE-Cadherin, anemia, Didff, DE-CAD, DE-Cad, DE-cadherin, DFF2, CG9414, 40kDa, GAT, Aconitate decarboxylase, l(2)k10220., shg/DE-Cad, DNA fragmentation factor 40 kDa subunit, cad, D E-cad, cold antibody hemolytic anaemia, PYR1, E-cadherin, Caspase-activated deoxyribonuclease, AI323667, gp150, E-cad, hemolytic, DFF-40, DEC, DmelCG3722, Cis-aconitic acid decarboxylase, Coronary Artery Disease, dCAD, DRORUD, CT12481, com5, CG1759, e-cad, DCad, ECad2, E-CAD, E-CadHeart, "Fredrickson type IIa hyperlipoproteinemia" EXACT [MTHICD9_2006:272.0], Familial Defective, Malformation Of Hearts, CDH, Materials, Disorders, LDL Receptor Disorder, Type IIa, Hlb301, Essential Hypercholesterolemia, determination, Coronary Diseases, Autosomal Dominant Hypercholesterolemia, Coronary, Dominant Hypercholesterolemias, CG11121, Mutations, Relative, Techniques, Personal, "type II hyperlipidemia" EXACT [NCI2004_11_17:C34704], abnormalities, old, sampling, diseases, congenital, Method, Associations, Heart Disease, Hyper-Low, diseases and disorders, Congenital Heart Defects, 2310040B03Rik, Psychological, Congenital Heart Diseases, human disease, Apolipoprotein B-100, heart-congenital defect, Genomes, Combined Hyperlipoproteinemia, Chip, ChIP, Hypercholesterolemias, Familial Combined, Defects, CHIP, Familial, Defect, SO, Social, genetic, Hyper-Low Density Lipoproteinemia, "familial hyperbetalipoproteinaemia" EXACT [SNOMEDCT_2005_07_31:190776000], chip, heart abnormality, SOSIE, Methodological Studies, Dominant Hypercholesterolemia, AW046544, Homo sapiens disease, stage, Social Power, Nucleotide, CG34352, So, Chd, CHD, Power, CG12139, Autosomal, "familial hypercholesterolemia (disorder)" EXACT [SNOMEDCT_2005_07_31:398036000], Apolipoprotein B 100, Familial Hypercholesterolemias, Density Lipoproteinemia, Coronary Heart Disease, Coronary Heart Diseases, l(2)k04405, wide/broad, Dmel_CG34339, Hypercholesterolemic Xanthomatoses, familial, Psychological Powers, Procedure, CG30368, Familial Combined 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Psychological Power, other disease, Procedures, Balearic Islands, Professional Power, Hyper-beta-Lipoproteinemias, Receptor Disorders, Abnormality, developmental stage, 2210017D18Rik, dCHIP, defect, Gene, Kingdom of the Netherlands, Heart Diseases, SCAR16, broad, Familial Ligand Defective, Hyperbetalipoproteinemia, Congenital Heart Disease, CG15316, method, Kingdom of Norway, Xanthomatoses, Isle of Man, Lipoproteinemias, DmelCG5203, DmelCG11121, heredity, method used in an experiment, Studies, disease or disorder, Hypercholesterolemia, Type IIa Hyperlipoproteinemias, defects, Technique, Essential Hypercholesterolemias, Coronary Heart, "Fredrickson type IIa lipidaemia" EXACT [SNOMEDCT_2005_07_31:190772003], type II hyperlipidemia, study, Hyperlipoproteinemia Type IIb, Hyperlipoproteinemia Type IIa, somda, NY-CO-7, Genetic, "familial hypercholesteremia" EXACT [CSP2005:1849-4634], congenital heart, Hyperlipoproteinemia, Familial Hypercholesterolemic Xanthomatoses, Congenital Heart, Hyperlipoproteinemias, Hyper-Low Density Lipoproteinemias, Hyperlipoproteinemia Type IIs, Heart Abnormality, U.K., non-neoplastic, Autosomal Dominant Hypercholesterolemias, Study, Sardinia, 1.1.99.1, Type II Hyperlipoproteinemia, Malformation Of Heart, Clients, Disorder, heart defect, DmelCG3924, Dm CG33087, Hypercholesterolemic Xanthomatosis, Hyper-Low-Density-Lipoproteinemias, disorder, Hyper-Low-Density-Lipoproteinemia, LDL Receptor Disorders, UBOX1, 0610033N24Rik, constitutitional genetic, PP1131, Drl, Congenital Heart Defect, CG12654, Disease, coronary arteriosclerosis, DmelCG33087, RnBP, Males, Essential, disorders, CG5203, Canary Islands, Great Britain, GlcNAc 2-epimerase, medical condition, Hyperbetalipoproteinemias, "familial hypercholesterolemia (disorder)" EXACT [SNOMEDCT_2005_07_31:31654005], Hyper-Low Density, l(2)04405, Cistrons, Client, Mdu, Xanthomatosis, Familial Combined Hyperlipoproteinemias, CG34339, N-acetyl-D-glucosamine 2-epimerase, Dmel_CG12139, mda, heart, chemical analysis, condition, Hyperlipoproteinemia Type 2, Professional, malformation Of, ami, Relative Risk, FHC, "Fredrickson type IIa hyperlipoproteinemia (disorder)" EXACT [SNOMEDCT_2005_07_31:397915002], Type II Hyperlipoproteinemias, Malformation Of, Power (Psychology)., "familial hyperbetalipoproteinaemia" EXACT [SNOMEDCT_2005_07_31:389985001], heart abnormalities, Ldb, LDB, med, Risks, Chromatin Immunoprecipitation, LDL, Heart Abnormalities, CG3924, Heart Defect, Holland, Hyper beta Lipoproteinemia, plan specification, CT7830, Combined Hyperlipoproteinemias, Personal Power, sample collection, dLDB/Chip, CG42611, Power (Psychology), renin-binding protein, lrp1, assay, Type II, hereditary, Hyper-beta-Lipoproteinemia, Females, CG8706Clinical Study Case, True Case Status, Case., Packaging Case, Case Dosing Unit, case, CASEfalseFH+CAD - samplesGencode case samples using 550K2015-01-29 09:39:28EGAD00010000578960624916650EGAC00001000182EGAS00001000734