Tag Archive for 'GWAS'

Incorporating false discovery rates into genetic association in autism

03/11/2014
Categories: Guest Posts
Written by

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?
Continue reading ‘Incorporating false discovery rates into genetic association in autism’

Tags: , , , , .
Closed

Eight types of schizophrenia? Not so fast…

30/09/2014
Categories: Analysis and Guest Posts
Written by

Editor’s note: this guest post was contributed by ten leading psychiatric geneticists (see author list at the end of the post) in response to the headline-grabbing claims of a recent paper claiming to have identified eight genetic sub-types of schizophrenia. Similar text has also been posted on PubMed Commons and elsewhere. [DM]

In a study published on September 15, Arnedo et al. asserted that schizophrenia is a heterogeneous group of disorders underpinned by different genetic networks mapping to differing sets of clinical symptoms. As a result of their analyses, Arnedo et al. have made remarkable and perhaps unprecedented claims regarding their capacity to subtype schizophrenia. This paper has received considerable media attention. One claim features in many media reports, that schizophrenia can be delineated into “8 types”. If these claims are replicable and consistent, then the work reported in this paper would constitute an important advance into our knowledge of the etiology of schizophrenia.

Unfortunately, these extraordinary claims are not justified by the data and analyses presented. Their claims are based upon complex (and we believe flawed) analyses that are said to reveal links between clusters of clinical data points and patterns of data generated by looking at millions of genetic data points. Instead of the complexities favored by Arnedo et al., there are far simpler alternative explanations for the patterns they observed. We believe that the authors have not excluded important alternative explanations – if we are correct, then the major conclusions of this paper are invalidated.
Continue reading ‘Eight types of schizophrenia? Not so fast…’

Tags: , , , .
Closed

A rare variant in Mexico with far-reaching implications

11/06/2014
Categories: Guest Posts
Written by

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.
Continue reading ‘A rare variant in Mexico with far-reaching implications’

Tags: , , , , , , .
Closed

The undiscovered chromosome

07/02/2014
Categories: Guest Posts
Written by

ChrXSexDiffPicBlackCroppedThis guest post was contributed by Taru Tukiainen, a postdoctoral research fellow in the Analytic and Translational Research Unit at Massachusetts General Hospital and the Broad Institute of MIT and Harvard.

The X chromosome contains around 5% of DNA in the human genome, but has remained largely unexplored in genome-wide association studies (GWAS) – to date, roughly two thirds of GWAS have thrown the X-chromosomal data out of their analyses. In a paper published in PLOS Genetics yesterday we dig into X chromosome associations and demonstrate why this stretch of DNA warrants particular attention in genetic association and sequencing studies. This post will focus on one of our key results: the possibility that some of the X chromosome loci contribute to sexual dimorphism, i.e. biological differences between men and women.
Continue reading ‘The undiscovered chromosome’

Tags: , , , , .
1 Comment

Looking closer at natural selection in inflammatory bowel disease

19/11/2012
Categories: Analysis
Written by

As I mentioned a few weeks ago, we recently published a large study into the genetics of inflammatory bowel disease (IBD), which included a number of analyses digging into the biology and evolutionary history of IBD genetic risk. Gratifyingly, our paper has stimulated a lot of discussion among other scientists, which has generated several ideas about future directions for this work. One question that was raised by several population-genetics experts at ASHG was about our natural selection analysis, and in particular our claim to discover an enrichment of balancing selection in IBD loci. In the paper, we found clear signals of natural selection on IBD loci, a subset of which we interpreted as balancing selection. In this post I will set out how I came to this conclusion, but then outline another explanation that could explain the results: recent local positive selection in Europeans.

Continue reading ‘Looking closer at natural selection in inflammatory bowel disease’

Tags: , , , , , .
2 Comments

Dozens of new IBD genes, but can they predict disease?

02/11/2012
Categories: Disease Risk
Written by

Out in Nature this week is a paper by three Genomes Unzipped authors reporting 71 new genetic associations with inflammatory bowel disease (IBD). This breaks the record for the largest number of associations for any common disease, and includes many new and interesting biological insights that you should all go and read about in the paper itself (pay-to-access I’m afraid) or on the Sanger Institute’s website.

One thing that we did not discuss in the paper was genetic prediction of IBD (i.e. using the risk variants we have discovered to predict who will or will not develop the disease). In this post I want to outline some of the situations in which we have considered using genetic risk prediction of IBD, and discuss whether any of them would actually work in practice.

Continue reading ‘Dozens of new IBD genes, but can they predict disease?’

Tags: , , , , , , , .
12 Comments

Size matters, and other lessons from medical genetics

23/11/2011
Categories: Journal Club
Written by , , and

Size really matters: prior to the era of large genome-wide association studies, the large effect sizes reported in small initial genetic studies often dwindled towards zero (that is, an odds ratio of one) as more samples were studied. Adapted from Ioannidis et al., Nat Genet 29:306-309.

[Last week, Ed Yong at Not Exactly Rocket Science covered a paper positing an association between a genetic variant and an aspect of social behavior called prosociality. On Twitter, Daniel and Joe dismissed this study out of hand due to its small sample size (n = 23), leading Ed to update his post. Daniel and Joe were then contacted by Alex Kogan, the first author of the study in question. He kindly shared his data with us, and agreed to an exchange here on Genomes Unzipped. In this post, we expand on our point about the importance of sample size; Alex’s reply is here.

Edit 01/12/11 (DM): The original version of this post included language that could have been interpreted as an overly broad attack on more serious, well-powered studies in psychiatric disease genetics. I’ve edited the post to reduce the possibility of collateral damage. To be clear: we’re against over-interpretation of results from small studies, not behavioral genetics as a whole, and I apologise for any unintended conflation of the two.]

In October of 1992, genetics researchers published a potentially groundbreaking finding in Nature: a genetic variant in the angiotensin-converting enzyme ACE appeared to modify an individual’s risk of having a heart attack. This finding was notable at the time for the size of the study, which involved a total of over 500 individuals from four cohorts, and the effect size of the identified variant–in a population initially identified as low-risk for heart attack, the variant had an odds ratio of over 3 (with a corresponding p-value less than 0.0001).

Readers familiar with the history of medical association studies will be unsurprised by what happened over the next few years: initial excitement (this same polymorphism was associated with diabetes! And longevity!) was followed by inconclusive replication studies and, ultimately, disappointment. In 2000, 8 years after the initial report, a large study involving over 5,000 cases and controls found absolutely no detectable effect of the ACE polymorphism on heart attack risk. In the meantime, the same polymorphism had turned up in dozens of other association studies for a wide range of traits ranging from obstet­ric cholestasis to menin­go­­coccal disease in children, virtually none of which have ever been convincingly replicated.
Continue reading ‘Size matters, and other lessons from medical genetics’

Tags: , , .
18 Comments

Friday Links: Studying association studies, and success at last in psychiatric genetics

07/10/2011
Categories: Friday Links
Written by

In PLoS Genetics this week there is a viewpoint article on data sharing in disease genetics. The authors systematically looked at 643 genome-wide association studies published between 2002 and 2010, to see how easily available the results of the studies are now. They found that the availability of full study results has gone down over time, and many groups that do share data have put more restrictions in place on its use. They put this down to fears over the privacy of research subjects, and in particular to the Homer et al study. The Homer et al result is somewhat complicated, but in essence it says that if you have stolen someone’s genotype data, you can use it to figure out if they have participated in any given research study by looking at the full results of the study.

It certainly seems possible that worries about privacy are reducing the free flow of information within the research community. However, whether on balance the decrease in information flow is worth the increase in security is an open question. For my own view, I feel that having the genome-wide results of genome-wide association studies freely available is very important to the field, and is more important than the the rather esoteric risk of someone stealing someone’s DNA and using it to figure out that they once took part in a research study of inflammatory bowel disease. [LJ]

Genome-wide association studies have been hugely successful in identifying dozens of common genetic risk factors for a large number of common diseases. However, one area that GWAS has not had much success in is the field of psychiatric illness, where finding common risk factors that replicate across studies has been consistently difficult. However, it looks like this is starting to change. The current issue of Nature Genetics has two papers from the Psychiatric GWAS Consortium, detailing some of the largest meta-analyses of schizophrenia and bipolar disease ever published.

The schizophrenia study robustly replicated two previously implicated variants, and discovered five new ones, and the bipolar disease study replicated one and discovered a new one. The new variants give us some pretty startling insights into the genetics of the diseases, in particular revealing the importance of a non-coding gene micro-RNA 137 in regulating a wide range of genes expressed in neurons. As always, these variants explain only a small proportion of the total genetic effect, but they show that psychiatric genetics has now truly entered the GWAS arena, with all the scientific benefits that this can bring to medical research. [LJ]

The images above, in order, are taken from the paper Temporal Trends in Results Availability from Genome-Wide Association Studies, and from Wikimedia Commons.

Tags: , , , , , , .
4 Comments

How do variants outside genes influence disease risk?

14/04/2011
Categories: Journal Club
Written by

Over the last several years, the number of genetic variants unambiguously associated with disease risk has grown dramatically. However, interpreting these signals has been extremely difficult—most of the identified variants do not disrupt genes, and indeed many don’t fall anywhere near genes (this observation has even led some to discount these signals entirely). To an investigator interested in following up on these signals, this is somewhat depressing: how can we hope to explore how polymorphisms affect disease risk if they don’t seem to fall in any sort of genome annotation that we understand?

In this context, I thought I’d point to an important paper that, among many other things, gives the first systematic evidence that variants which influence disease are not just randomly scattered across the genome, but instead tend to fall in particular regions—in particular, enhancer elements (regions where DNA-binding proteins interact with DNA to influence gene expression).

The authors rely on the fact that, in the cell, DNA is wrapped around proteins called histones, which control how accessible the DNA is to things like transcription factors (see above figure). These proteins can be chemically modified, and it is now clear that particular patterns of modifications are predictive of the function of the DNA in the region—some modifications indicate transcribed genes, others regions of enhancer activity, others repressed regions, etc.

What the authors did in this study was generate genome-wide maps of several histone modifications in nine different cell types, and use this data to predict the function of each 200 base pair segment of the human genome in each cell type. There are a number of interesting analyses of these “maps” of genome function in the paper, but for our purposes here there’s one of particular interest: the authors took sets of SNPs associated with various diseases and simply asked, are these variants enriched in regions with any particular functional prediction? And indeed, for several phenotypes, there is a striking enrichment of association signals in enhancers elements in a relevant cell type. For example, SNPs which influence lipid levels are enriched in enhancers in a liver cancer cell line, and SNPs which influence the autoimmune disease lupus are enriched in enhancers in a lymphoblastoid cell line.

As these types of functional maps are generated in more cell types, I imagine there will be more stories like this. The problem with interpreting disease association studies, it seems likely, is largely due to our lack of understanding of genome function.

—-
Citation: Ernst et al. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. doi:10.1038/nature09906

Tags: , .
4 Comments

Analysing your own genome, bloggers respond to the FDA and more reporting on bogus GWAS results

18/03/2011
Categories: Friday Links
Written by and

Razib Khan, more known for his detailed low-downs of population biology and history, has written an important post on Gene Expression, explaining in careful detail exactly how to run some simple population genetic analysis on public genomes, as well as on your own personal genomics data. The outcome of the tutorial is an ADMIXTURE plot (like the one to the left), showing what proportion of your genome comes from different ancestral populations. This sort of analysis is not difficult, but it can often be hard to know how to start, so Razib’s post gives a good landing point for people who want to dig deaper into their own genomes.

This tutorial also ties in to some political ideas that Razib has been talking about since the recent call to allow access to genomic information only via prescription. If you are worried about losing access to your genome, one option is to ensure that you do not require companies to generate and interpret your genome. As sequencing, genotyping and computing prices fall, DIY genetics becomes more and more plausible. Learn to discover things about your own genome, and no-one will be able to take that away from you. [LJ]

Continue reading ‘Analysing your own genome, bloggers respond to the FDA and more reporting on bogus GWAS results’

Tags: , , , , , , , , .
1 Comment

Page optimized by WP Minify WordPress Plugin