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Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample.

Ng E, Salihovic S, Lind PM, Mahajan A, Syvänen AC, Axelsson T, Ingelsson E, Lindgren CM, van Bavel B, Morris AP, Lind L - Environ. Res. (2015)

Bottom Line: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects.Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2.In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Electronic address: esther.ng@well.ox.ac.uk.

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(a) Regional Association plot of PCB 99. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (b) Regional Association plot of PCB 138. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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f0010: (a) Regional Association plot of PCB 99. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (b) Regional Association plot of PCB 138. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Mentions: Following imputation, a total of 8,736,858 high-quality SNPs with MAF >1% were included in the analysis. The genomic control inflation factor for each PCB congener was close to 1 (Table 1), so no additional correction for residual population structure after adjustment for principal components was required. We identified genome-wide significant evidence of association for plasma levels of PCB-99, mapping to CYP2B6. The SNP with the strongest association signal was rs8109848 (β=0.34, SE=0.05, p=3.7×10−13), which maps to an intronic region of CYP2B6 (Fig. 1 and 2, Supplemental Tables S1 and S2). This SNP also showed weaker association with several other PCBs (Supplemental Table S3) including PCB-138 (p=3.0×10−8) and PCB-153 (p=0.000041). Conditional analyses, including the genotype dosage of rs8109848 as a covariate in the regression model, extinguished the association signal for all PCBs at this locus.


Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample.

Ng E, Salihovic S, Lind PM, Mahajan A, Syvänen AC, Axelsson T, Ingelsson E, Lindgren CM, van Bavel B, Morris AP, Lind L - Environ. Res. (2015)

(a) Regional Association plot of PCB 99. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (b) Regional Association plot of PCB 138. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4509719&req=5

f0010: (a) Regional Association plot of PCB 99. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (b) Regional Association plot of PCB 138. Each point represents a SNP plotted with their p-value (on a −log10 scale) as a function of genomic position (NCBI Build 37). In each panel, the lead SNP is represented by the purple diamond. The colour coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r2 from the 1000 Genomes Project March 2012 release): red r2≥0.8; gold 0.6≤r2<0.8; green 0.4≤r2<0.6; cyan 0.2≤r2<0.4; blue r2<0.2; grey r2 unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Mentions: Following imputation, a total of 8,736,858 high-quality SNPs with MAF >1% were included in the analysis. The genomic control inflation factor for each PCB congener was close to 1 (Table 1), so no additional correction for residual population structure after adjustment for principal components was required. We identified genome-wide significant evidence of association for plasma levels of PCB-99, mapping to CYP2B6. The SNP with the strongest association signal was rs8109848 (β=0.34, SE=0.05, p=3.7×10−13), which maps to an intronic region of CYP2B6 (Fig. 1 and 2, Supplemental Tables S1 and S2). This SNP also showed weaker association with several other PCBs (Supplemental Table S3) including PCB-138 (p=3.0×10−8) and PCB-153 (p=0.000041). Conditional analyses, including the genotype dosage of rs8109848 as a covariate in the regression model, extinguished the association signal for all PCBs at this locus.

Bottom Line: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects.Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2.In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Electronic address: esther.ng@well.ox.ac.uk.

Show MeSH
Related in: MedlinePlus