A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r(2) of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r(2) of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62863/1/nature06258.pd

Performance of multiparametric MRI appears better when measured in patients who undergo radical prostatectomy

Nancy N Wang,1 Richard E Fan,1 John T Leppert,1,2 Pejman Ghanouni,3 Christian A Kunder,4 James D Brooks,1 Benjamin I Chung,1 Geoffrey A Sonn1,3 1Department of Urology, Stanford University School of Medicine, Stanford, CA, USA; 2Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA, USA; 3Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA; 4Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA Abstract: Utilization of pre-biopsy multiparametric MRI (mpMRI) is increasing. To optimize the usefulness of mpMRI, physicians should accurately quote patients a numerical risk of cancer based on their MRI. The Prostate Imaging Reporting and Data System (PIRADS) standardizes interpretation of mpMRI; however, reported rates of clinically significant prostate cancer (CSC) stratified by PIRADS score vary widely. While some publications use radical prostatectomy (RP) specimens as gold standard, others use biopsy. We hypothesized that much of the variation in CSC stems from differences in cancer prevalence in RP cohorts (100% prevalence) vs biopsy cohorts. To quantify the impact of this selection bias on cancer yield according to PIRADS score, we analyzed data from 614 men with 854 lesions who underwent targeted biopsy from 2014 to 2018. Of these, 125 men underwent RP. We compared the PIRADS detection rates of CSC (Gleason ≥7) on targeted biopsy between the biopsy-only and RP cohorts. For all PIRADS scores, CSC yield was much greater in patients who underwent RP. For example, CSC was found in 30% of PIRADS 3 lesions in men who underwent RP vs 7.6% in men who underwent biopsy. Our results show that mpMRI performance appears to be better in men who undergo RP compared with those who only receive biopsy. Physicians should understand the effect of this selection bias and its magnitude when discussing mpMRI results with patients considering biopsy, and take great caution in quoting CSC yields from publications using RP as gold standard. Keywords: counseling, image-guided biopsy, magnetic resonance imaging, patient selection, prostatic neoplasm

Correction: Learning from the “tail end” of de-implementation: the case of chemical castration for localized prostate cancer (Implementation Science Communications, (2021), 2, 1, (124), 10.1186/s43058-021-00224-8)

Following the publication of the original article [1] the authors requested to update the “Competing interests” section as follows: “The authors declare that Anne Sales is co-Editor-in-Chief of the journal".http://deepblue.lib.umich.edu/bitstream/2027.42/177471/2/Correction Learning from the tail end of de-implementation the case of chemical castration for localized prostate cancer.pdfAccepted versionDescription of Correction Learning from the tail end of de-implementation the case of chemical castration for localized prostate cancer.pdf : Published versio