How to interpret a genome-wide association study. JAMA, 299, 1335-1344. Erratum in: JAMA, 299, 2150

Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-2154, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 04/2008; 299(11):1335-44. DOI: 10.1001/jama.299.11.1335
Source: PubMed

ABSTRACT Genome-wide association (GWA) studies use high-throughput genotyping technologies to assay hundreds of thousands of single-nucleotide polymorphisms (SNPs) and relate them to clinical conditions and measurable traits. Since 2005, nearly 100 loci for as many as 40 common diseases and traits have been identified and replicated in GWA studies, many in genes not previously suspected of having a role in the disease under study, and some in genomic regions containing no known genes. GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors. Although these studies are clearly many steps removed from actual clinical use, and specific applications of GWA findings in prevention and treatment are actively being pursued, at present these studies mainly represent a valuable discovery tool for examining genomic function and clarifying pathophysiologic mechanisms. This article describes the design, interpretation, application, and limitations of GWA studies for clinicians and scientists for whom this evolving science may have great relevance.

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Available from: Teri Manolio, May 30, 2014
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    • "While well controlled negative association studies need to be published and are in many ways as valuable as positive associations , lack of replication cannot be assumed unless the same phenotype is assayed in a population of the same structure [147]. In addition to prove accurate collection of phenotype and genotype data, demonstration of positive associations with genes known to be linked to the condition lends the cohort credence [148]. Due to the lack of clearly linked positive control genes it is currently difficult to assess the quality of negative association data although this situation should improve. "
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    • "Traditional clinical diagnosis and management focuses on the individual patient's symptoms, medical history, and data from laboratory and imaging evaluation to diagnose and treat illnesses. Recent new developments in human disease have provided us with a more detailed understanding of the disease in individual subject, such as, single nucleotide polymorphisms (SNP) and genome-wide association studies (GWAS) [28] [29]. Based on the new extension, targeting identification and drug discovery is an emerging clinical application area for drug-resistance tumor disease and unknown-treatment genetic disease and some rare disease, which is called as personalized therapy [30]. "
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    • "Ludwig and colleagues also performed analyses separating NSCLO and NSCLP, finding that rs8001641 (13q31.1) is uniquely associated with NSCLP [Ludwig et al., 2012]. A current challenge in human genetics is identifying specific etiologic variants following GWA studies, which identify regions or SNPs associated with the disease but may not have identified the causative variant due to linkage disequilibrium that results in tested SNPs serving as surrogates for other untested variants [Pearson and Manolio, 2008; Manolio, 2010]. Many of the SNPs associated with NSCL/P are located in gene deserts or far from the nearest gene, leading to the hypothesis that regulatory variants contribute to the risk of NSCL/P. "
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    ABSTRACT: Genome wide association (GWA) studies have successfully identified at least a dozen loci associated with orofacial clefts. However, these signals may be unique to specific populations and require replication to validate and extend findings as a prelude to etiologic SNP discovery. We attempted to replicate the findings of a recent meta-analysis of orofacial cleft GWA studies using four different ancestral populations. We studied 946 pedigrees (3,436 persons) of European (US white and Danish) and Asian (Japanese and Mongolian) origin. We genotyped six SNPs that represented the most significant P-value associations identified in published studies: rs742071 (1p36), rs7590268 (2p21), rs7632427 (3p11.1), rs12543318 (8q21.3), rs8001641 (13q31.1), and rs7179658 (15q22.2). We directly sequenced three non-coding conserved regions 200 kb downstream of SPRY2 in 713 cases, 438 controls, and 485 trios from the US, Mongolia, and the Philippines. We found rs8001641 to be significantly associated with nonsyndromic cleft lip with cleft palate (NSCLP) in Europeans (P-value = 4 × 10(-5) , ORtransmission = 1.86 with 95% confidence interval: 1.38-2.52). We also found several novel sequence variants in the conserved regions in Asian and European samples, which may help to localize common variants contributing directly to the risk for NSCLP. This study confirms the prior association between rs8001641 and NSCLP in European populations. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2015; 167(5). DOI:10.1002/ajmg.a.36912 · 2.16 Impact Factor
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