Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

PatternCNV: a versatile tool for detecting copy number changes from exome sequencing data.

MOTIVATION: Exome sequencing (exome-seq) data, which are typically used for calling exonic mutations, have also been utilized in detecting DNA copy number variations (CNVs). Despite the existence of several CNV detection tools, there is still a great need for a sensitive and an accurate CNV-calling algorithm with built-in QC steps, and does not require a paired reference for each sample. RESULTS: We developed a novel method named PatternCNV, which (i) accounts for the read coverage variations between exons while leveraging the consistencies of this variability across different samples; (ii) reduces alignment BAM files to WIG format and therefore greatly accelerates computation; (iii) incorporates multiple QC measures designed to identify outlier samples and batch effects; and (iv) provides a variety of visualization options including chromosome, gene and exon-level views of CNVs, along with a tabular summarization of the exon-level CNVs. Compared with other CNV-calling algorithms using data from a lymphoma exome-seq study, PatternCNV has higher sensitivity and specificity. AVAILABILITY AND IMPLEMENTATION: The software for PatternCNV is implemented using Perl and R, and can be used in Mac or Linux environments. Software and user manual are available at http://bioinformaticstools.mayo.edu/research/patterncnv/, and R package at https://github.com/topsoil/patternCNV/.

Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.

BACKGROUND: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging. OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Blood samples from 11 506 men in Sweden were collected during 1991-1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1×10-6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis. RESULTS AND LIMITATIONS: We found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p<5×10-8) and replicated in an independent cohort: rs73055188 (p=5.27×10-9, per-allele hazard ratio [HR]=2.27, 95% confidence interval [CI] 1.72-2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p<1×10-6) and replicated in an independent cohort: rs2702185 (p=7.1×10-7, per-allele HR=2.55, 95% CI=1.76-3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups. CONCLUSIONS: The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer. PATIENT SUMMARY: We identify two genetic markers that are associated with prostate-cancer-specific survival time.

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer.

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Progress toward an efficient panel of SNPs for ancestry inference.

Many panels of ancestry informative single nucleotide polymorphisms have been proposed in recent years for various purposes including detecting stratification in biomedical studies and determining an individual's ancestry in a forensic context. All of the panels have limitations in their generality and efficiency for routine forensic work. Some panels have used only a few populations to validate them. Some panels are based on very large numbers of SNPs thereby limiting the ability of others to test different populations. We have been working toward an efficient and globally useful panel of ancestry informative markers that is comprised of a small number of highly informative SNPs. We have developed a panel of 55 SNPs analyzed on 73 populations from around the world. We present the details of the panel and discuss its strengths and limitations.