ABSTRACT
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.
Subject(s)
Antigen Presentation , Genes, MHC Class I , HIV Infections/genetics , HIV Infections/immunology , HIV-1 , HLA-B Antigens/genetics , Black or African American/genetics , Alleles , Amino Acids/physiology , CD8-Positive T-Lymphocytes/immunology , Cohort Studies , Disease Progression , Genome-Wide Association Study , HIV Antigens/immunology , HIV Infections/ethnology , HIV Infections/virology , HIV Long-Term Survivors , HIV-1/immunology , HLA-A Antigens/chemistry , HLA-A Antigens/genetics , HLA-A Antigens/immunology , HLA-A Antigens/metabolism , HLA-B Antigens/chemistry , HLA-B Antigens/immunology , HLA-B Antigens/metabolism , HLA-C Antigens/chemistry , HLA-C Antigens/genetics , HLA-C Antigens/immunology , HLA-C Antigens/metabolism , Haplotypes , Hispanic or Latino/genetics , Humans , Immunity, Innate , Logistic Models , Models, Molecular , Polymorphism, Single Nucleotide , Protein Conformation , Viral Load , White People/geneticsABSTRACT
Discovering the molecular basis of mitochondrial respiratory chain disease is challenging given the large number of both mitochondrial and nuclear genes that are involved. We report a strategy of focused candidate gene prediction, high-throughput sequencing and experimental validation to uncover the molecular basis of mitochondrial complex I disorders. We created seven pools of DNA from a cohort of 103 cases and 42 healthy controls and then performed deep sequencing of 103 candidate genes to identify 151 rare variants that were predicted to affect protein function. We established genetic diagnoses in 13 of 60 previously unsolved cases using confirmatory experiments, including cDNA complementation to show that mutations in NUBPL and FOXRED1 can cause complex I deficiency. Our study illustrates how large-scale sequencing, coupled with functional prediction and experimental validation, can be used to identify causal mutations in individual cases.
Subject(s)
Electron Transport Complex I/genetics , Genetic Association Studies , Mitochondrial Diseases/genetics , Mitochondrial Proteins/genetics , Mutation/genetics , Blotting, Western , Case-Control Studies , Gene Dosage , Humans , Mitochondrial Proteins/metabolism , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Subject(s)
Adiposity , Body Fat Distribution , Genome-Wide Association Study , Lysophospholipase/genetics , Obesity/genetics , Oxidoreductases/genetics , Transcription Factor AP-2/genetics , Adult , Cohort Studies , Female , Humans , Male , Methionine Sulfoxide Reductases , Obesity/metabolism , Polymorphism, Single Nucleotide , Waist Circumference , Waist-Hip RatioABSTRACT
Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
