Rare genetic variants explain missing heritability in smoking

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (hSNP2) was estimated from 0.13 to 0.28 (s.e., 0.10–0.13) in European ancestries, with 35–74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5–4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability (hped2, 0.18–0.34). In the African ancestry samples, hSNP2 was estimated from 0.03 to 0.33 (s.e., 0.09–0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking

Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1\ud as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of\ud NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1\ud for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa