Tag Archive for 'rare variants'

Incorporating false discovery rates into genetic association in autism

This guest post was contributed by Joseph Buxbaum, Mark Daly, Silvia De Rubeis, Bernie Devlin, Kathryn Roeder, and Kaitlin Samocha from the Autism Sequencing Consortium (see affiliations and details at the end of the post).

Autism spectrum disorder (ASD) is a highly heritable condition characterized by deficits in social communication, and by the presence of repetitive behaviors and/or stereotyped interests. While it is clear from family and twin studies that genetic factors contribute strongly to the onset of this disorder, the search for specific risk genes for ASD has only recently begun to yield fruit. Finding these specific genes is critical not only for providing potential diagnoses for individual families, but also for obtaining insights into the pathological processes that underlie this neurodevelopmental disorder, which may ultimately lead to novel therapeutic approaches. Identification of ASD genes may at some point also reveal part of what makes us social beings.

In a paper published in Nature last week we and the other members of the Autism Sequencing Consortium (ASC) describe the application of whole exome sequencing (WES), selectively sequencing the coding regions of the genome, to identify rare genetic variants and then genes associated with risk for ASD. WES data were analyzed from nearly 4,000 individuals with autism and nearly 10,000 controls. In these analyses, we identify and subsequently analyze a set of 107 autosomal genes with a false discovery rate (FDR) of <30%; in total, this larger set of genes harbor de novo loss of function (LoF) mutations in 5% of cases, and numerous de novo missense and inherited LoF mutations in additional cases. Three critical pathways contributing to ASD were identified: chromatin remodelling, transcription and splicing, and synaptic function. Chromatin remodelling controls events underlying neural connectivity. Risk variation also impacted multiple components of synaptic networks. Because a wide set of synaptic genes is disrupted in ASD, it seems reasonable to suggest that altered chromatin dynamics and transcription, induced by disruption of relevant genes, leads to impaired synaptic function as well.

In this post we wanted to focus on an easily-overlooked aspect of this paper: the use of a false discovery rate (FDR) approach to identifying genes for follow-up analysis. While FDR is a well-recognized approach in biology, one could also argue for using a family wise error rate (FWER), which has been the norm in recent large-scale, genome-wide association studies (GWAS). So why did we decide to take this alternative approach here?
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A rare variant in Mexico with far-reaching implications

HNF1A-imageThis guest post was contributed by Karol Estrada, a postdoctoral research fellow in the Analytic and Translational Research Unit at Massachusetts General Hospital and the Broad Institute of MIT and Harvard. It is dedicated to the memory of Laura Riba.

Genome-wide association studies (GWAS) of common variants have successfully implicated more than 70 genomic regions in type 2 diabetes, revealing new biological pathways and potential drug targets. However, most large studies have examined genetic variation only in northwestern European populations, despite the rich genetic diversity in other populations around the world. Most studies have also been limited in their ability to detect variants present in fewer than 5 percent of people. Much remains to be learned.

In this post, we discuss our new paper, published in the Journal of the American Medical Association, on a low-frequency missense variant in the gene HNF1A that raises risk of type 2 diabetes five-fold, and was seen only in Latinos. This variant was the only rare variant to reach genome-wide significance in an exome sequencing study of almost 4,000 people, the largest such study to date. We explain the ramifications for sample sizes of rare-variant studies, note the importance of studying populations outside of northwestern Europe, and caution against simplistic dichotomous interpretations of disease as either complex or monogenic. Finally, we note that a low-frequency or rare variant might guide therapeutic modification.
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