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Science Summary: Response to Predicting the Diagnosis of Autism Spectrum Disorder Using Gene Pathway Analysis

Science post imageLetter to the Editor

Molecular Psychiatry advance online publication 22 October 2013; doi: 10.1038/mp.2013.125

Response to ‘Predicting the diagnosis of autism spectrum disorder using gene pathway analysis’
Open

E B Robinson1,2,3, D Howrigan1,2,3, J Yang4,5, S Ripke1,2,3,6, V Anttila1,2,3,6, L E Duncan3,7,8,9, L Jostins10, J C Barrett10, S E Medland11, D G MacArthur1,2,3, G Breen12, M C O'Donovan13, N R Wray4,5, B Devlin14, M J Daly1,2,3,6, P M Visscher4,5, P F Sullivan15 and B M Neale1,2,3,6

    1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
    2Department of Medicine, Harvard Medical School, Boston, MA, USA
    3Medical and Population Genetics Program, Broad Institute for Harvard and MIT, Cambridge, MA, USA
    4The University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia
    5The Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
    6Stanley Center for Psychiatric Research, Broad Institute for Harvard and MIT, Cambridge, MA, USA
    7Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
    8Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts, General Hospital, Boston, MA, USA
    9Department of Psychiatry, Harvard Medical School, Boston, MA, USA
    10Wellcome Trust Sanger Institute, Cambridge, UK
    11Queensland Institute of Medical Research, Brisbane, QLD, Australia
    12Social Genetic and Developmental Psychiatry Center, Institute of Psychiatry, King’s College London, London, UK
    13MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Cardiff, UK
    14Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    15Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Correspondence: BM Neale, E-mail: bneale@broadinstitute.org

In a recent paper published online in Molecular Psychiatry, Skafidas et al.1 report a classifier for identifying individuals at risk for autism spectrum disorders (ASDs). Their classifier is based on 267 single-nucleotide polymorphisms (SNPs) that were selected from the results of a pathway analysis using cases from the Autism Genetic Resource Exchange (AGRE).1 Using within-sample cross-validation, the authors claim a classification accuracy for ASDs of 85.6%. They subsequently applied their classifier to ASD cases from the Simons Foundation Autism Research Initiative (SFARI) and controls from the Wellcome Trust Birth Cohort (WTBC) and report ASD classification accuracy of 71.7%.

We believe that the claims made by Skafidas et al.1 are inconsistent with current knowledge of the genetics of ASDs,2 and inconsistent with the expected precision of risk predictions for complex psychiatric disorders. Further, as classification accuracy depends on the size of the discovery sample, the results are also inconsistent with the size of the sample they employed (only 123 controls were included in the discovery set).


To examine the validity of Skafidas et al.’s claims, we pursued a range of analyses to assess the evidence for association between ASDs and (1) the individual SNPs named in their paper as most predictive, (2) their genetic classifier, to the extent it was described and (3) the pathways identified in the report, from which the predictive SNPs were selected. For each analysis, where possible, we attempted to replicate the analytic approach of Skafidas et al.1 using data from the Psychiatric Genomics Consortium (PGC) autism group, which includes ~5400 cases, more than three times the number used in the original report. The methodology of these analyses is described in detail in Supplementary Information.

First, we found no evidence for single SNP associations between any of the 30 most contributory SNPs listed by Skafidas et al.1 in their Table 2 and ASDs in the PGC (Table 1). In the current PGC meta-analysis, the mean P-value for these SNPs was 0.47 with a minimum 0.007, and none are notable or survive a 30 SNP correction for multiple testing. Further information on these associations can be found in Supplementary Information. 

Read the full letter at Nature.com.

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The science category is sponsored by AutismFreeBrain, Inc.  AFB was created to fund innovative research to develop a cure for Autism Spectrum Disorders (ASD). Our studies have identified inflammatory processes in the brain, we called Brain Immunity Storms, that are much like an allergic reaction, releasing surges of molecules that disrupt areas of the brain responsible for emotion and language.

Comments

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Jenny

What was the reasoning for the Skafidas groups to not provide
the full list of SNPs? Why was their control groups so woefully small - is it hard to find unaffected individuals anymore since so many have been injured? Exactly where did the controls come from?
Were any of the SNPs used the mthfr SNPs or were they excluded?
Have any other groups been attempting to validate their results? They would/will certainly need reexamination, also.

cmo

With all the success of genetic research, would it not make sense to simply scrap the polio vaccine

and look for the gene that causes some children to get polio and some children not to ???

This might only take 10 or 15 years...

Betty

Interesting, Stewart. Is it possible doppler radar has its influence through the microbiome? Maybe contributing to the gut dysbiosis that is so common in autism?

Lou

Science Summary: Response to Predicting the Diagnosis of Autism

I have a simple autism prediction method.

NO "vaccination" little to no autism

"Vaccination" autism in a dose dependent manner

This hypothesis is very easy to test. It has been tested MANY times epidemiologically, most recently in India, and found to hold each and every time.

http://dr-king.com/docs/100711_ParallelsinNewDelhiIndia_AnEpidemic_b.pdf

Benedetta

What about the gut troubles of most of those with autism, and the fact that in trying to make a cholera vaccine -- they gave people celiacs?

http://blog.glutenfreeclub.com/the-path-from-cholera-to-celiac-disease

This blog makes it sound all roses --- oh look we were making a vaccine for cholera - but failed -- and yet it was a discovery for a new pharm med.

Doppler there?

Linda

Stewart,
Have you shared your findings with any scientists already working in this area, like Dr. David Carpenter at University of Albany or autism specialist Dr. Martha Herbert or any of the other contributors to the BioInitiative Report? Also, see the scientists at ElectromagneticHealth.org. Another possible resource would be Pong chief science officer, Rong Wang, PhD who is an expert on human cellular responses to radiation. Her bio: www.pongresearch.com/about-us/leadership-bios.html

Stewart Simonson

Guys,

I think it is the doppler radar towers emitting 0.25 MW - 1.25 MWs of high frequency radiation into the atmosphere which is in turn attenuating it and reflecting back to Earth as low frequency penetrating, ionizing radiation. The doppler towers appear to be triggering higher incidence of algae blooms and fish/mammal kills around the Towers in Florida and around the country. I have lots of google earth plots on my blog

South Korea has the highest flux of doppler and highest incidence of autism 1/38

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