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Genomics In The Journals: Jul 14, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A large international research group tracked down seven new loci associated with prostate cancer in the third phase of its multi-stage genome-wide association study. The team tested more than 1,500 SNPs in 4,574 individuals with the disease and 4,164 without before whittling the top 10 new candidate loci to seven sites by genotyping tens of thousands of samples collected for 30 studies. The researchers, who identified 16 other prostate cancer risk loci in the previous two stages of the study, shared their latest findings in Nature Genetics.

"With the identification of these new loci, more than 40 susceptibility loci for [prostate cancer] have now been identified," co-senior author Rosalind Eeles, a researcher with the Institute of Cancer Research and the Royal Marsden National Health Service Foundation in the UK, and her co-authors wrote. "When previously reported loci are included, approximately 25 percent of familial risk in [prostate cancer] can now be explained."

In another Nature Genetics study, members of the Wellcome Trust Case Control Consortium 2 and the Australo-Anglo-American Spondyloarthritis Consortium (TASC) report on GWAS findings for ankylosing spondylitis, a form of inflammatory arthritis. The WTCCC2 and TASC researchers combined their data to get genotype information on 3,023 ankylosing spondylitis cases and 8,779 controls. They then did follow-up analyses on another 2,111 case and 4,483 control samples from the Spondyloarthritis Research Consortium of Canada.

In the process, the researchers found several new and previously identified risk loci, including changes affecting a number of inflammatory and immune-related genes. They also got clues about genetic changes corresponding to forms of the disease involving the presence or absence of the human leukocyte antigen HLA-B27. For instance, their results indicate that variants in the endoplasmic reticulum aminopeptidase gene ERAP1 only associate with ankylosing spondylitis in the HLA-B27-positive cases.

In the New England Journal of Medicine, members of the PodoNet Consortium describe how they used linkage analyses and targeted sequencing to find a pair of mutations in the myosin gene MYO1E in individuals with focal segmental glomerulosclerosis, a disease involving local lesions in the kidney that affect the organ's filtration functions. The investigators detected the first MYO1E mutation using whole-genome linkage analyses, followed by sequence capture and targeted Roche 454 GS FLX sequencing on individuals from an Italian family with three affected children. They subsequently found the second disease-associated MYO1E mutation in another family with two affected children. Neither mutation turned up in unaffected control individuals from Italy and Turkey.

"These mutations are closely associated with autosomal recessive focal segmental glomerulosclerosis," the team wrote, "and several findings support their potential causative role in the development of this disorder."

Glitches in VPS35, a vacuolar protein sorting associated gene that codes for a component of an intracellular sorting and transport complex called the retromer complex, can contribute to inherited Parkinson disease, according to two American Journal of Human Genetics studies.

An international team used Knome sequencing services to get exome sequences for two members of a Swiss family affected by autosomal-dominant, late onset Parkinson disease. The analysis uncovered a VPS35 mutation in the affected first cousins — a genetic change that subsequently turned up in seven more affected members from that family and in individuals from three other families who had the disease. Researchers did not detect the change in more than 3,300 unaffected controls.

"Our study implicated disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to [Parkinson disease]," senior author Matthew Farrer, a researcher affiliated with the University of British Columbia and the Mayo Clinic in Jacksonville, Florida, and co-authors wrote.

Meanwhile, researchers from Germany and Austria used exome sequencing to find VPS35 mutations in an Austrian family with inherited, late-onset Parkinson disease. That team found six more non-synonymous changes to the gene when they screened 860 more individuals with Parkinson disease and 1,014 controls, including three mutations found exclusively in those affected by the disease.

The Scan

UK Pilot Study Suggests Digital Pathway May Expand BRCA Testing in Breast Cancer

A randomized pilot study in the Journal of Medical Genetics points to similar outcomes for breast cancer patients receiving germline BRCA testing through fully digital or partially digital testing pathways.

Survey Sees Genetic Literacy on the Rise, Though Further Education Needed

Survey participants appear to have higher genetic familiarity, knowledge, and skills compared to 2013, though 'room for improvement' remains, an AJHG paper finds.

Study Reveals Molecular, Clinical Features in Colorectal Cancer Cases Involving Multiple Primary Tumors

Researchers compare mismatch repair, microsatellite instability, and tumor mutation burden patterns in synchronous multiple- or single primary colorectal cancers.

FarGen Phase One Sequences Exomes of Nearly 500 From Faroe Islands

The analysis in the European Journal of Human Genetics finds few rare variants and limited geographic structure among Faroese individuals.