title: Contribution of genome-wide association studies to scientific research: a pragmatic approach to evaluate their impact.
abstract: The factual value of genome-wide association studies (GWAS) for the understanding of multifactorial diseases is a matter of intense debate. Practical consequences for the development of more effective therapies do not seem to be around the corner. Here we propose a pragmatic and objective evaluation of how much new biology is arising from these studies, with particular attention to the information that can help prioritize therapeutic targets. We chose multiple sclerosis (MS) as a paradigm disease and assumed that, in pre-GWAS candidate-gene studies, the knowledge behind the choice of each gene reflected the understanding of the disease prior to the advent of GWAS. Importantly, this knowledge was based mainly on non-genetic, phenotypic grounds. We performed single-gene and pathway-oriented comparisons of old and new knowledge in MS by confronting an unbiased list of candidate genes in pre-GWAS association studies with those genes exceeding the genome-wide significance threshold in GWAS published from 2007 on. At the single gene level, the majority (94 out of 125) of GWAS-discovered variants had never been contemplated as plausible candidates in pre-GWAS association studies. The 31 genes that were present in both pre- and post-GWAS lists may be of particular interest in that they represent disease-associated variants whose pathogenetic relevance is supported at the phenotypic level (i.e. the phenotypic information that steered their selection as candidate genes in pre-GWAS association studies). As such they represent attractive therapeutic targets. Interestingly, our analysis shows that some of these variants are targets of pharmacologically active compounds, including drugs that are already registered for human use. Compared with the above single-gene analysis, at the pathway level GWAS results appear more coherent with previous knowledge, reinforcing some of the current views on MS pathogenesis and related therapeutic research. This study presents a pragmatic approach that helps interpret and exploit GWAS knowledge.
authors: Centre for Experimental Neurological Therapies-CENTERS-S. Andrea Hospital-Site, Department of Neuroscience, Mental Health and Sensory Organs, NESMOS, "Sapienza", University of Rome, Roma, Italy.
authors: Vito A G
authors: VA
authors: Ricigliano
authors: Renato
authors: R
authors: Umeton
authors: Lorenzo
authors: L
authors: Germinario
authors: Eleonora
authors: E
authors: Alma
authors: Martina
authors: M
authors: Briani
authors: Noemi
authors: N
authors: Di Segni
authors: Dalma
authors: D
authors: Montesanti
authors: Giorgia
authors: G
authors: Pierelli
authors: Fabiana
authors: F
authors: Cancrini
authors: Cristiano
authors: C
authors: Lomonaco
authors: Francesca
authors: F
authors: Grassi
authors: Gabriella
authors: G
authors: Palmieri
authors: Marco
authors: M
authors: Salvetti
mesh_terms: D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D012106:Research
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