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Germline Sequence Variants in TGM3 and RGS22 Confer Risk of Basal Cell Carcinoma

Simon N Stacey et al. Hum Mol Genet. .
Free PMC article


To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.


Figure 1.
Figure 1.
Association signals at the (A) TGM3 and (B) RGS22 loci. The upper panels show the BCC association signals [expressed as −log10(P)] for variants identified by whole-genome sequencing and imputation. Positions of key single nucleotide polymorphisms discussed in the text are indicated. The middle panel shows recombination rates calculated as described previously (39). The lower panel shows the locations of RefSeq genes in the region.
Figure 2.
Figure 2.
The BCC risk allele rs214782[G] is associated with reduced expression of TGM3 in blood-derived RNA. (A) Expression of TGM3 RNA for three genotypes of rs214782, measured in RNA from whole blood samples from 963 individuals using Agilent microarrays. The expression is shown as 10(average MLR) where MLR is the mean log expression ratio and the average is over individuals with the indicated genotype. The vertical bars indicate the s.e.m. Significance was determined by regressing the MLR values against the number of risk alleles that each individual carries, adjusting for age, sex, familial relatedness and differential cell count in blood. (B) For confirmation, a subset of 168 RNA samples from (A) were tested using RT-PCR and analysed similarly.

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