Journal article
Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder
Journal of neurodevelopmental disorders, v 16(1), 54
12 Sep 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS.BACKGROUNDCommon genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS.We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants.METHODSWe studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants.Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric.RESULTSPrior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric.The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries.LIMITATIONSThe studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries.We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.CONCLUSIONSWe show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.
Metrics
Details
- Title
- Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder
- Creators
- Michael Yao - Bloomberg (United States)Jason Daniels - Bloomberg (United States)Luke Grosvenor - Center for Autism and Related DisordersValerie Morrill - Bloomberg (United States)Jason I Feinberg - Center for Autism and Related DisordersKelly M Bakulski - University of Michigan–Ann ArborJoseph PivenHeather C Hazlett - University of North Carolina at Chapel HillMark D Shen - University of North Carolina at Chapel HillCraig Newschaffer - Drexel UniversityKristen Lyall - Drexel UniversityRebecca J Schmidt - University of California, DavisIrva Hertz-PicciottoLisa A Croen - Kaiser PermanenteM Daniele Fallin - Emory UniversityChristine Ladd-AcostaHeather Volk - Center for Autism and Related DisordersKelly Benke - Center for Autism and Related Disorders
- Publication Details
- Journal of neurodevelopmental disorders, v 16(1), 54
- Publisher
- BMC
- Number of pages
- 12
- Grant note
- Centers for Disease Control and Prevention (CDC): 01086, 02199, DD11-002, DD06-003, DD04-001, DD09-002 NIH: R01 HD055741 Simons Foundation: 140209
This work was supported by Centers for Disease Control and Prevention (CDC) Cooperative Agreements announced under the following RFAs: 01086, 02199, DD11-002, DD06-003, DD04-001, and DD09-002. IBIS was supported by grants from NIH R01 HD055741 (ACE), Autism Speaks, and Simons Foundation (140209) The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:001310832700001
- Scopus ID
- 2-s2.0-85203704282
- Other Identifier
- 991021903961804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Clinical Neurology
- Neurosciences