Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Genome-wide expression analysis in fibroblast cell lines from probands with Pallister Killian syndrome.

Pallister Killian syndrome (OMIM: # 601803) is a rare multisystem disorder typically caused by tissue limited mosaic tetrasomy of chromosome 12p (isochromosome 12p). The clinical manifestations of Pallister Killian syndrome are variable with the most common findings including craniofacial dysmorphia, hypotonia, cognitive impairment, hearing loss, skin pigmentary differences and epilepsy. Isochromosome 12p is identified primarily in skin fibroblast cultures and in chorionic villus and amniotic fluid cell samples and may be identified in blood lymphocytes during the neonatal and early childhood period. We performed genomic expression profiling correlated with interphase fluorescent in situ hybridization and single nucleotide polymorphism array quantification of degree of mosaicism in fibroblasts from 17 Caucasian probands with Pallister Killian syndrome and 9 healthy age, gender and ethnicity matched controls. We identified a characteristic profile of 354 (180 up- and 174 down-regulated) differentially expressed genes in Pallister Killian syndrome probands and supportive evidence for a Pallister Killian syndrome critical region on 12p13.31. The differentially expressed genes were enriched for developmentally important genes such as homeobox genes. Among the differentially expressed genes, we identified several genes whose misexpression may be associated with the clinical phenotype of Pallister Killian syndrome such as downregulation of ZFPM2, GATA6 and SOX9, and overexpression of IGFBP2

Schematic illustration of disease mechanism of PKS.

<p>Schematic illustration of disease mechanism of PKS.</p

Ingenuity pathway analysis of dysregulated genes in PKS.

<p>Green circles represent the genes down-regulated in PKS probands, and red circles represent the genes up-regulated in PKS probands.</p

BOX plot of HOX gene clusters.

<p>HOX A is down- and HOX B Cluster is up-regulated in PKS patients.</p

List of upregulated genes on 12p in PKS probands.

<p>List of upregulated genes on 12p in PKS probands.</p

Patient and control sample clustering.

<p>Red squares/circles represent PKS patients and Green squares/circles represent control samples. (A) Unsupervised clustering of 26 samples using all genes. (B) Unsupervised clustering of 26 samples using genes located on 12p.(C) PCA result. Proportion of Variance % (PC1-24.818, p 0.001; PC2-17.814, p 0.022; PC3-0.022, p 0.772).</p

Sample/mosaic ratio information.

<p>Sample/mosaic ratio information.</p

Gene expression levels in PKS.

<p><b>a</b>: Mosaic 12p expression level correlation: Average expression of 171 genes on 12p in patients and controls. Red bars are patients and Grey is controls. X-axis represents samples and Y-axis shows average expression of genes on 12p. <b>b</b>: Level of i12p mosaicism compared to 12p gene expression: average of 64 genes with expression higher than the 3rd quartile of global expression distribution, were correlated to mosaicism%. The blue line in the figure is the fitting line of linear regression. Red diamonds are the probands and green are the controls.</p