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A screen of 1,049 schizophrenia and 30 Alzheimer’s-associated variants for regulatory potential

Leslie Myint, Ruihua Wang, Leandros Boukas, Kasper D. Hansen, Loyal A. Goff, Dimitrios Avramopoulos
doi: https://doi.org/10.1101/447557
Leslie Myint
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
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Ruihua Wang
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine
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Leandros Boukas
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine
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Kasper D. Hansen
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine
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Loyal A. Goff
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine
3Department of Neuroscience, Johns Hopkins School of Medicine
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Dimitrios Avramopoulos
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine
4Department of Psychiatry, Johns Hopkins School of Medicine
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  • For correspondence: adimitr1@jhmi.edu
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Abstract

Recent genome-wide association studies (GWAS) identified numerous schizophrenia (SZ) and Alzheimer’s disease (AD) associated loci, most outside protein-coding regions and hypothesized to affect gene transcription. We used a massively parallel reporter assay (MPRA) to screen, 1,049 SZ and 30 AD variants in 64 and 9 loci respectively for allele differences in driving reporter gene expression. A library of synthetic oligonucleotides assaying each allele 5 times was transfected into K562 chronic myelogenous leukemia lymphoblasts and SK-SY5Y human neuroblastoma cells. 148 variants showed allelic differences in K562 and 53 in SK-SY5Y cells, on average 2.6 variants per locus. Nine showed significant differences in both lines, a modest overlap reflecting different regulatory landscapes of these lines that also differ significantly in chromatin marks. Eight of nine were in the same direction. We observe no preference for risk alleles to increase or decrease expression. We find a positive correlation between the number of SNPs in Linkage Disequilibrium (LD) and the proportion of functional SNPs supporting combinatorial effects that may lead to haplotype selection. Our results prioritize future functional follow up of disease associated SNPs to determine the driver GWAS variant(s), at each locus and enhance our understanding of gene regulation dynamics.

Footnotes

  • ↵& Now at the Department of Mathematics, Statistics, and Computer Science, Macalester College

  • Funding sources: NIMH R56MH113215 and P50MH094268 (project 1) to DA

  • The authors have no conflicts of interest to declare

  • Minor wording and formatting revisions and minor changes in analytical process

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 05, 2019.
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A screen of 1,049 schizophrenia and 30 Alzheimer’s-associated variants for regulatory potential
Leslie Myint, Ruihua Wang, Leandros Boukas, Kasper D. Hansen, Loyal A. Goff, Dimitrios Avramopoulos
bioRxiv 447557; doi: https://doi.org/10.1101/447557
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A screen of 1,049 schizophrenia and 30 Alzheimer’s-associated variants for regulatory potential
Leslie Myint, Ruihua Wang, Leandros Boukas, Kasper D. Hansen, Loyal A. Goff, Dimitrios Avramopoulos
bioRxiv 447557; doi: https://doi.org/10.1101/447557

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