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Population structure confounds autism genetic classifier

Molecular Psychiatry volume 19, pages 405–407 (2014)Cite this article

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A classifier was recently reported to predict with 70% accuracy if an individual has an autism spectrum disorder using 237 single-nucleotide polymorphisms (SNPs).1 Biomarkers, genetic or otherwise, that would facilitate earlier autism spectrum disorder diagnosis are crucial; therefore, these results warrant careful scrutiny. One potential confounder of such genetic studies is bias when cases and controls have different ancestral origins. Here, we show that the largest components of this classifier’s autism risk score distinguish populations, but do not separate cases from controls. In short, the frequencies of reported risk and protective alleles do not differ between related individuals with or without autism in independent data sets; instead, they reflect ancestral origin. Specifically, cases have more diverse ancestral origins within Europe than controls. The putative risk alleles are more common in the Northeastern than in the Northwestern Europe, whereas the putative protective alleles reflect the opposite trend. Likewise, we find that the autism risk scores based on the strongest SNPs do not differ between people with and without autism in an independent data set, but that they do differ between European populations.

We then asked if the cases and controls have different ancestral origins. If so, population structure would be correlated with autism in the sample, leading to the faulty conclusion that genetic variants that differentiate populations instead mediate autism risk. Much of the genetic diversity among Europeans reflects geography.4 To attempt to control for population structure, the classifier’s authors excluded individuals whose genomes better-reflected HapMap3 populations other than CEU (a Western and Northern European population). For example, because an Italian population (TSI) was included in HapMap3, their removal reduced bias that could be introduced from different Northern and Southern origins in cases and controls within Europe. In both training and validation sets, the cases were European Americans who have diverse ancestral origins, whereas the controls were explicitly intended to represent populations in Northwestern Europe (CEU and a British birth cohort). This raised the concern that genetic differences between Eastern and Western Europeans could be a major confound.

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Authors and Affiliations

  1. Center for Autism Research and Treatment, and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA

    T G Belgard, J K Lowe & D H Geschwind

  2. Department of Human Genetics, University of California, Los Angeles, CA, USA

    I Jankovic & D H Geschwind

  3. Department of Neurology, Program in Neurogenetics, University of California, Los Angeles, CA, USA

    J K Lowe & D H Geschwind

Authors
  1. T G Belgard
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  2. I Jankovic
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  3. J K Lowe
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  4. D H Geschwind
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Corresponding author

Correspondence to D H Geschwind.

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Competing interests

DHG is on the scientific advisory board of Synapdx. All other authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Belgard, T., Jankovic, I., Lowe, J. et al. Population structure confounds autism genetic classifier. Mol Psychiatry 19, 405–407 (2014). https://doi.org/10.1038/mp.2013.34

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