Limits...
Effects of copy number variable regions on local gene expression in white blood cells of Mexican Americans.

Blackburn A, Almeida M, Dean A, Curran JE, Johnson MP, Moses EK, Abraham LJ, Carless MA, Dyer TD, Kumar S, Almasy L, Mahaney MC, Comuzzie A, Williams-Blangero S, Blangero J, Lehman DM, Göring HH - Eur. J. Hum. Genet. (2015)

Bottom Line: We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs.Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity.As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center San Antonio, San Antonio, TX, USA.

ABSTRACT
Only few systematic studies on the contribution of copy number variation to gene expression variation have been published to date. Here we identify effects of copy number variable regions (CNVRs) on nearby gene expression by investigating 909 CNVRs and expression levels of 12059 nearby genes in white blood cells from Mexican-American participants of the San Antonio Family Heart Study. We empirically evaluate our ability to detect the contribution of CNVs to proximal gene expression (presumably in cis) at various window sizes (up to a 10 Mb distance) between the gene and CNV. We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs. Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity. As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level. We find that genes whose expression level is significantly influenced by nearby CNVRs are enriched for immunity and autoimmunity related genes. These findings add to the currently limited catalog of CNVRs that are recognized as expression quantitative trait loci, and have implications for future study designs as well as for prioritizing candidate causal variants in genomic regions associated with disease.

No MeSH data available.


Related in: MedlinePlus

Window size and statistically significant tests. The top panel shows the distribution of the distances between the gene and CNV for the tests performed using a 10 Mb window size. The middle panel shows the tests that were statistically significant (q<0.1) among the tests performed at a 10 Mb window size. The statistically significant results are clearly enriched for proximity between genes and CNVs. The bottom panel shows the number of statistically significant tests (vertical axis, q<0.1) for various window sizes in increments of 100 kb up to 10 Mb. The benefit of increasing window size to capture additional cis effects is outweighed by correction of multiple testing around a window size of 1.2 Mb.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4538210&req=5

fig2: Window size and statistically significant tests. The top panel shows the distribution of the distances between the gene and CNV for the tests performed using a 10 Mb window size. The middle panel shows the tests that were statistically significant (q<0.1) among the tests performed at a 10 Mb window size. The statistically significant results are clearly enriched for proximity between genes and CNVs. The bottom panel shows the number of statistically significant tests (vertical axis, q<0.1) for various window sizes in increments of 100 kb up to 10 Mb. The benefit of increasing window size to capture additional cis effects is outweighed by correction of multiple testing around a window size of 1.2 Mb.

Mentions: In order to identify which CNVs are putative cis-eQTL, we tested the aforementioned 909 CNVs for association with transcript levels of genes within a symmetrical 10 Mb window of each CNV (a total window size of 20 Mb+CNV length). In total, we analyzed 89 893 CNV-expression probe pairs. As expected, we detected a substantial number of significant eQTL, after adjusting for multiple testing. As shown in Figure 2, significant findings were enriched for proximity between CNVs and genes. The most highly-associated CNV-gene pair was between GSTM1 and an overlapping duplication, and was detected using two separate gene expression probes. This duplication was estimated to account for ~52% of the variance in GSTM1 expression by both probes (Figure 1).


Effects of copy number variable regions on local gene expression in white blood cells of Mexican Americans.

Blackburn A, Almeida M, Dean A, Curran JE, Johnson MP, Moses EK, Abraham LJ, Carless MA, Dyer TD, Kumar S, Almasy L, Mahaney MC, Comuzzie A, Williams-Blangero S, Blangero J, Lehman DM, Göring HH - Eur. J. Hum. Genet. (2015)

Window size and statistically significant tests. The top panel shows the distribution of the distances between the gene and CNV for the tests performed using a 10 Mb window size. The middle panel shows the tests that were statistically significant (q<0.1) among the tests performed at a 10 Mb window size. The statistically significant results are clearly enriched for proximity between genes and CNVs. The bottom panel shows the number of statistically significant tests (vertical axis, q<0.1) for various window sizes in increments of 100 kb up to 10 Mb. The benefit of increasing window size to capture additional cis effects is outweighed by correction of multiple testing around a window size of 1.2 Mb.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538210&req=5

fig2: Window size and statistically significant tests. The top panel shows the distribution of the distances between the gene and CNV for the tests performed using a 10 Mb window size. The middle panel shows the tests that were statistically significant (q<0.1) among the tests performed at a 10 Mb window size. The statistically significant results are clearly enriched for proximity between genes and CNVs. The bottom panel shows the number of statistically significant tests (vertical axis, q<0.1) for various window sizes in increments of 100 kb up to 10 Mb. The benefit of increasing window size to capture additional cis effects is outweighed by correction of multiple testing around a window size of 1.2 Mb.
Mentions: In order to identify which CNVs are putative cis-eQTL, we tested the aforementioned 909 CNVs for association with transcript levels of genes within a symmetrical 10 Mb window of each CNV (a total window size of 20 Mb+CNV length). In total, we analyzed 89 893 CNV-expression probe pairs. As expected, we detected a substantial number of significant eQTL, after adjusting for multiple testing. As shown in Figure 2, significant findings were enriched for proximity between CNVs and genes. The most highly-associated CNV-gene pair was between GSTM1 and an overlapping duplication, and was detected using two separate gene expression probes. This duplication was estimated to account for ~52% of the variance in GSTM1 expression by both probes (Figure 1).

Bottom Line: We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs.Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity.As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center San Antonio, San Antonio, TX, USA.

ABSTRACT
Only few systematic studies on the contribution of copy number variation to gene expression variation have been published to date. Here we identify effects of copy number variable regions (CNVRs) on nearby gene expression by investigating 909 CNVRs and expression levels of 12059 nearby genes in white blood cells from Mexican-American participants of the San Antonio Family Heart Study. We empirically evaluate our ability to detect the contribution of CNVs to proximal gene expression (presumably in cis) at various window sizes (up to a 10 Mb distance) between the gene and CNV. We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs. Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity. As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level. We find that genes whose expression level is significantly influenced by nearby CNVRs are enriched for immunity and autoimmunity related genes. These findings add to the currently limited catalog of CNVRs that are recognized as expression quantitative trait loci, and have implications for future study designs as well as for prioritizing candidate causal variants in genomic regions associated with disease.

No MeSH data available.


Related in: MedlinePlus