Showing papers by "Stephan Ripke published in 2010"
TL;DR: Differences in binding to viral peptide antigens by HLA may be the major factors underlying genetic differences between HIV controllers and progressors, and genome-wide association results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
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.
1,038 citations
Harvard University1, Broad Institute2, QIMR Berghofer Medical Research Institute3, King's College London4, Radboud University Nijmegen Medical Centre5, University of Würzburg6, State University of New York Upstate Medical University7, University of Marburg8, Cardiff University9, Aarhus University Hospital10, University of Basel11, University of Zurich12, Goethe University Frankfurt13, University of Trier14, Trinity College, Dublin15, University of St Andrews16, VU University Amsterdam17, Ghent University18, Semel Institute for Neuroscience and Human Behavior19, University of Pennsylvania20, Children's Hospital of Philadelphia21, Washington University in St. Louis22, University of Valencia23, Hebrew University of Jerusalem24, University of Göttingen25, University of Duisburg-Essen26, University of Southampton27, New York University28, Eli Lilly and Company29, Pfizer30, University of California, Los Angeles31
TL;DR: This paper conducted a meta-analysis of existing studies to boost statistical power and found no genome-wide significant associations, although an analysis of candidate genes suggests that they may be involved in the disorder.
Abstract: Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.
467 citations
TL;DR: A genome-wide association study of advanced age-related macular degeneration cases and controls using the Affymetrix 6.0 platform implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.
Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.
427 citations
Harvard University1, Massachusetts Institute of Technology2, QIMR Berghofer Medical Research Institute3, Trinity College, Dublin4, Medical Research Council5, Radboud University Nijmegen Medical Centre6, University of St Andrews7, State University of New York Upstate Medical University8, Cardiff University9, University of Würzburg10, University of Marburg11, University of Zurich12, Goethe University Frankfurt13, University of Trier14, University of Göttingen15, VU University Amsterdam16, Ghent University17
TL;DR: The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles.
Abstract: Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genomewide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. Results: No genomewide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1. Conclusions: The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(9):906‐920. Key Words: ADHD, genetics, genome-wide association, imputation
169 citations
TL;DR: Associations of CFHR1–CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent.
Abstract: Associations of CFHR1–CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent
59 citations
TL;DR: The findings suggest that TPH2 polymorphisms characterize a subgroup of depressed patients who are especially prone to develop metabolic disorders induced by a genotype-dependent impairment of serotonergic neurotransmission.
Abstract: Major depression and the metabolic syndrome (MetS) are interacting clinical conditions influenced by genetic susceptibility. For both disorders, impaired serotonergic neurotransmission in specific brain areas has been suggested. This led us to investigate whether variants in the gene coding for tryptophan hydroxylase 2 (TPH2), the brain-specific and rate-limiting enzyme for serotonin biosynthesis, might be predictive for an increased liability for the development of MetS in depressed patients. In a case-control study consisting of 988 patients with recurrent unipolar depression (RUD) and 1023 psychiatric healthy controls, MetS components were ascertained according to the International Diabetes Foundation criteria. A total of 41 single nucleotide polymorphisms fully covering the TPH2 gene region were genotyped in stage 1 (300 patients/300 controls), resulting in significant genetic associations of polymorphisms located in exon 7 and intron 8 of TPH2 and the occurrence of MetS in depressed patients after correction for age, gender and multiple testing (51 RUD-MetS/179 RUD-non-MetS). We were able to confirm the significant association of rs17110690 in stage 2 (688 patients/723 controls; 110 RUD-MetS/549 RUD-non-MetS) and to link risk-genotypes and risk-haplotypes for MetS to lower TPH2 mRNA expression and to lower 5-hydroxyindoleacetic acid levels in cerebrospinal fluid previously reported in functional studies. Our findings suggest that TPH2 polymorphisms characterize a subgroup of depressed patients who are especially prone to develop metabolic disorders induced by a genotype-dependent impairment of serotonergic neurotransmission. Identifying depressed patients at high risk for MetS using genetic variants could have direct clinical impact on individualized disease management and prevention strategies.
34 citations