Tag Archive for 'exomes'

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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Guest Post: Jimmy Lin on community-funded rare disease genomics

Jimmy Cheng-Ho Lin, MD, PhD, MHS is the Founder/President of Rare Genomics Institute, helping patients with rare diseases design, source, and fund personalized genomics projects. He is also on the faculty in the Pathology and Genetics Departments at the Washington University in St. Louis, as part of the Genomics and Pathology Services. Prior to this, he completed his training with Bert Vogelstein and Victor Veculescu at Johns Hopkins and Mark Gerstein at Yale, and led the computational analysis of some of the first exome sequencing projects in any disease, including breastcolorectal, glioblastoma, and pancreatic cancers.

At Rare Genomics Institute (RGI), we have a dream: that one day any parent or community can help access and fund the latest technology for their child with any disease. While nonprofits and foundations exist for many diseases, the vast majority of the 7,000 rare diseases do not have the scientific and philanthropic infrastructure to help. Many parents fight heroically on behalf of their children, and some of them have even become the driving force for research. At RGI, we are inspired by such parents and feel that if we can help provide the right tools and partnerships, extraordinary things can be achieved.

We start by helping parents connect with the right researchers and clinicians. Then, we provide mechanisms for them to fundraise. Finally, we try to guide them through the science that hopefully result in a better life for their child or for future children. Throughout the whole process, we try to educate, support, and walk alongside families undergoing this long journey.
Continue reading ‘Guest Post: Jimmy Lin on community-funded rare disease genomics’

Friday Links

The Genomes Unzipped team has been quiet for the last few weeks as we prepare for a major announcement – stay tuned next week to find out more. In the meantime, here are a few things we found around the web this week.

China’s sequencing powerhouse BGI collaborated with Danish researchers to analyse the exomes (the sequences of all protein-coding genes) of 200 individuals from Denmark, in a study published in Nature Genetics. The researchers took an approach similar to that adopted by the 1000 Genomes Project, sequencing each of the individuals at fairly low depth (with each base in the exome being covered on average by 12 sequencing reads, as compared to at least 30 for a “high quality” genome), but then using a statistical approach to identify variants and infer their frequency within the population. The headline finding was that the sequenced individuals carry more rare protein-altering polymorphisms than expected; the authors conclude:

Based on our findings, we support the idea that much of the heritable variation affecting fitness is caused by low-frequency mutations, which are often overlooked in studies based on genotyping rather than resequencing.

The conclusion that much of the “missing heritability” for disease is driven by rare protein-altering mutations is plausible, but this study in and of itself doesn’t provide compelling evidence in support of it. Fortunately, more definitive studies are underway: as tens of thousands of exomes from disease patients and controls accumulate over the next two years, the contribution of rare protein-coding variants to disease (or surprising lack thereof) will soon be fairly definitively established. [DM]

Bio-IT World has an excellent special issue on “The Road to the $1000 Genome”, highlights include an article pondering the often underestimated costs of analysis of genome sequences, and an update on Hugh Reinhoff’s personal quest to find the mutation underlying his daughter’s genetic disease. The issue coincides with the launch of editor Kevin Davies’ new book The $1000 Genome, which was favourably reviewed this week at 23andMe’s blog The Spittoon. [DM]

In Science this week, John Travis takes a look at the technically and ethically challenging world of Native American genetics, focusing on the effort to sequence the nuclear genome of Lakota warrior Sitting Bull from snippets allegedly taken from the man’s hair. The story includes the unusual method by which the main researcher in the project gained approval to study the Native American’s remains:

LaPointe said the basement ceremony was required to get permission from Sitting Bull himself, who was killed in 1890. Willerslev says something odd happened at the ceremony, recalling a blue-green light that ran across his body and into his mouth. LaPointe says the spirit of Sitting Bull tested the geneticist and approved. As a result, LaPointe allowed Willerslev to cut a short section from a long braid of Sitting Bull’s still-shiny black hair and fly it back to the University of Copenhagen for analysis.

If only all ethics committee meetings were livened up by pyrotechnics… [DM]

A piece in Fortune tells the remarkable story of Hugh Martin, CEO of the massively-funded third-generation sequencing startup Pacific Biosciences, who has battled openly with cancer while guiding the company through funding rounds and towards a public share offering. [DM]


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