Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure

Abstract

Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genomeediting in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure.

Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

“…On the other hand, we found only nominal enrichment of variants associated with coronary artery disease in fibroblasts and no enrichment of variants associated with heart failure in any cardiac cell type. These findings may reflect the heterogeneous etiologies of cardiovascular diseases and, in the case of heart failure, the limited number of currently known risk loci 42 . Future GWAS in large cohorts with detailed phenotyping, including biobanks such as the UK Biobank 56 and the BioBank Japan Project 57 and whole genome sequencing efforts such as the NHLBI Trans-Omics for Precision Medicine (TOPMed) program 58 , will help identify and refine disease association signals.…”

“…Non-coding genetic variants contributing to risk of complex diseases are enriched within cCREs in a cell type-specific fashion 20,[37][38][39][40] . To examine the enrichment of cardiovascular disease variants within cCREs active in specific cardiac cell types, we performed cell type-stratified LD (Linkage disequilibrium) score regression analysis 41 using GWAS summary statistics for cardiovascular diseases [42][43][44][45][46] ( Figure 5A Figure 5A). Next, to identify likely causal AF risk variants in cardiomyocyte cCREs, we first determined the probability that variants were causal for AF (Posterior probability of association, PPA) at 111 known loci using Bayesian fine-mapping 47 .…”

“…We used LD (linkage disequilibrium) score regression 41,105 to estimate genome-wide enrichment for variants associated with GWAS traits within cell type-resolved open chromatin sites. We compiled published GWAS summary statistics for cardiovascular diseases [42][43][44][45][46] , other diseases [106][107][108][109][110][111][112][113][114][115][116][117] , and non-disease traits [118][119][120][121][122][123][124][125][126][127] using the European subset from transethnic studies where applicable. We created custom LD score files by using peaks from each cluster as a binary annotation.…”

An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum

“…We obtained GWAS summary statistics for quantitative traits related to neurological disease and control traits: Heart Failure 96 , Type 1 Diabetes 97 , Age First Birth and Number Children Born 98 , Lupus 99 , Primary Biliary Cirrhosis 100 , Tiredness 101 , Crohns_Disease 102 , Inflammatory Bowel Disease 102 , Ulcerative_Colitis 102 , Asthma 103 , Attention Deficit Hyperactivity Disorder 104 , Heart Rate 105 , Celiacs Disease 106 , HOMA-B 107 , HOMA-IR 107 , Childhood Aggression 108 , Atopic Dermatitis 109 , Allergy 110 , HDL_Cholesterol 111 , LDL_Cholesterol 111 , Total Cholesterol 111 , Triglycerides 111 , Autism Spectrum Disorder 112 , Birth Weight 113 , Bipolar Disorder 114 , Multiple Sclerosis 115 , Insomnia 116 , Vitamin D 117 , Primary Sclerosing Cholangitis 118 , Vitiligo 119 , Chronotype 120 , Sleep Duration 120 , Alzheimer’s Disease 121 , BMI 122 , Neuroticism 123 , Type 2 Diabetes 124 , Stroke 125 , Fasting Glucose 126 , Fasting Insulin 126 , Child Sleep Duration 127 , Coronary Artery Disease 128 , Atrial Fibrillation 129 , Rheumatoid Arthritis 130 , Educational Attainment 131 , Chronic Kidney Disease 132 , Obsessive Compulsive Disorder 133 , Post Traumatic Stress Disorder 134 , Schizophrenia 135 , Age At Menopause 136 , Age At Menarche 137 , Tobacco use disorder (ftp://share.sph.umich.edu/UKBB_SAIGE_HRC/, Phenotype code: 318) 138 , Intelligence 139 , Alcohol Usage 140 , Fasting Proinsulin 141 , Head Circumference 142 , Microalbuminuria 143 , Extraversion 144 , Birth Length 145 , Amyotrophic Lateral Sclerosis 146 , Anorexia Nervosa 147 , HbA1c 148 , Major Depressive Disorder 149 , Height 150 .…”

The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology

“…Finally, in addition to Hspb1 , RNA-Seq also identified Actn2 (alpha actinin) among the downregulated genes in Tdrd7−/− lens. ACTN2 is an F-actin-binding protein, which in non-muscle cells is involved in facilitating F-actin–membrane interactions and is linked to cardiac defects ( 94 , 95 ). Our preliminary RT-qPCR data validates Actn2 as a significantly downregulated gene in Tdrd7−/− lens (data not shown).…”