*downloaded from public database(GSE62742)

When mapping molecular quantitative trait loci, genetic associations with traits such as gene expression are typically identified using linear additive genetic models. These models assume that the phenotype of heterozygotes is halfway between the low-homozygous and high-homozygous genotypes and may miss non-additive relationships, such as those caused by dominant alleles. Studies in Drosophila melanogaster and other model organisms have found evidence for non-additive genetic associations with enhancer activity and gene expression, and we hypothesized that these type of associations may also exist in the human genome (1). To map non-additive associations in the human genome, we applied a multiple linear regression model on single nucleotide polymorphisms (SNPs) from 1000 Genomes and ChIP-seq data from 62 Yoruba lymphoblaststoid cell lines (2).

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Number of reference allelesFig.1 Figure shows additive relationship between phenotypic and genotypic values

rs1079355 on chr 1 (p = 110-5)

where GA equals the number of reference alleles in each genotype and GD was assigned to be 1 for heterozygotes and 0 for homozygotes. Levels refer to the quantile normalized H3K27ac levels, which were then forced to be standard normal.

Identifying non-additive genetic associations with histone modifications and gene expression in human cell lines

Jing Gu, Patrick Fiaux, Graham McVicker *Department of Chemistry and Biochemistry, University of California, San Diego, CA 92093

Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037

Abstract

Statistical Model: Multi Linear RegressionLevels = GA

Pipeline Development

Acknowledgements & References

Results for Association Tests

I would like to thank Patrick for his support in developing pipelines. I also need to thank Dr. Graham McVicker for helping experiments design and data analysis. Lastly, I appreciated all the help from other people in McVicker’s lab. 1) T.E.Lum et al., Genetics, vol.189, 837-849(2011) 2) F. Grubert et al., Cell 162, 1051–1065 (2015)

Example of a Top SNP on Chromosome 12

• significant non-additive associations at a subset of loci from H3K27ac, H3K4me1, and H3K4me3

• Allele-specific analysis shows for balanced reads low-allele has increased levels of H3K27ac in

heterozygous individuals for imbalanced reads reads are biased toward the high-allele

suggesting that this allele may have increased activation in heterozygotes.

other situations include that for balanced reads heterozygous individuals have significant lower levels of H3K27ac than homozygous ones or for imbalanced reads reads are biased toward the low-allele.

Conclusion

mcvicker.salk.edu

Example of a Top SNP on Chromosome 8

H3K27AC H3K4ME3 H3K4ME1

Total SNPs 449001 369526 637050

Significant p value for beta2 (FDR = 10%) 60 17 174

Genotype-phenotype correlation

H3k

27ac

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(n = 17) (n = 30) (n = 14)

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Allele-specific analysis for heterozygotes

H3K27AC Marker

rs10797355

Fig.3 UCSC genome browser display of H3K27ac peak and top SNP rs10797355. Gene C1orf174 is a chromosome 1 open reading frame 174 mRNA, while gene LINC01134 is a long intergenic non-protein long coding RNA. Notice that both genes are close to each and express in opposite directions.

Genotype-phenotype correlation

H3k

27ac

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(n = 25) (n = 30) (n = 6)

rs36089630 on chr 8 (p = 1.510-6)

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Allele-specific analysis for heterozygotes

rs12824739

H3K27AC Marker

Fig.2 UCSC genome browser display of H3K27ac peak and top SNP rs36089630. Gene FAM86B3P is family with sequence similarity 86, member A pseudogene.

H3K27acH3K27ac H3K4ME1H3K4ME3

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-log10(actual p-value)