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JAMA Special Issue Focuses on Genomics in Medicine

NEW YORK (GenomeWeb News) – In a special issue of the Journal of the American Medical Association out today, researchers presented a set of studies, editorials, and viewpoint articles centered on a genomics theme.

In one of the studies, for instance, members of the Alzheimer Disease Genetic Consortium outlined findings from a meta-analysis focused on uncovering genetic variants linked to late-onset Alzheimer's disease risk in individuals of African-American ancestry.

The Columbia University-led group brought together data on 1,968 African-American individuals with Alzheimer's disease and more than 3,900 unaffected individuals from the same population. All of the cases and controls were at least 60 years old.

Using data at more than 17 million SNPs that had been directly genotyped or imputed in each of the individuals, the researchers tracked down Alzheimer's disease-associated loci in and around genes associated with late-onset forms of Alzheimer's disease in past studies of individuals of European ancestry, including the infamous APOE gene.

But the analysis also revealed particularly significant ties between late-onset Alzheimer's disease in the African-American population and a variant in an ATP-binding cassette transporter-coding gene called ABCA7.

"Aside from SNPs associated with APOE, the top-ranked SNP observed in this study was located in ABCA7," Columbia University's Richard Mayeux, corresponding author on the study, and his colleagues noted, "and had an effect size comparable with that of APOE [epsilon]4."

"This observation differs from the previous GWAS in whites," they added. "The reported ABCA7 SNPs in non-Hispanic whites have lower effect sizes … as do all other genes reported in whites."

"Pursuing research in an understudied ethnic group is important for scientific and for ethical reasons," Robert Nussbaum, a researcher with the University of California at San Diego's Institute for Human Genetics, wrote in an accompanying editorial.

Nussbaum also noted that the research shores up some of the genetic associations detected for late-onset Alzheimer's disease in the past, while highlighting pathways that are potentially important to development of the disease.

Even so, he cautioned that there is still more to be learned about the clinical utility of the risk variants in ABCA7 and other Alzheimer's-associated genes, since there is already debate about whether seemingly healthy individuals should be tested for the risky version of APOE when preventative treatments aren't available.

In another JAMA study, researchers from the UK and Germany described a culture-free, metagenomics method for tracking pathogenic bacteria involved in an Escherichia coli outbreak in Germany in 2011.

Using 45 fecal samples collected during the outbreak, the team tested the notion that metagenomic sequencing might prove useful for assessing outbreak bacterial strains — in this case, representative from a Shiga toxin-producing form of E. coli known as O104:H4

After generating bacterial sequences via high-throughput metagenomic sequencing, the investigators assembled a de novo genome assembly for the Shiga-toxigenic E. coli, or STEC.

For the subsequent stages of their analyses, they then looked at sequence coverage levels for each outbreak-associated strain, demonstrating that outbreak genomes in at least 10 samples had been covered to at least 10-fold coverage, while outbreak genomes in another 26 samples were sequenced to at least one-fold coverage, on average.

With the metagenomic data in hand, the group found a few outbreak samples that contained sequences from other pathogenic bacteria, too — from Clostridium difficile and Salmonella enterica to Campylobacter species.

"[T]hese results illustrate the potential of metagenomics as an open-ended, culture-independent approach for the identification and characterization of bacterial pathogens during an outbreak of diarrheal disease," University of Warwick microbiology and infection researcher Mark Pallen, the study's corresponding author, and his colleagues wrote.

"Challenges include speeding up and simplifying workflows, reducing costs, and improving diagnostic sensitivity," they continued, "all of which are likely to depend in turn on improvements in sequencing technologies."

An editorial addressing that study, provided by Stanford University's David Relman, touched on the sensitivity, significance, and clinical applicability of the metagenomics-based method for understanding pathogens involved in outbreaks.

"Microbial genome and community sequence data are destined to affect clinical and public health decision making in a profound manner," Relman concluded. "However, clinician-investigators know that there remain many critical, clinically relevant questions that demand more than genome sequence data, requiring biological measurements and a deeper understanding of the ecological and clinical setting."

An international team led by investigators at Johns Hopkins University looked at the role that the notorious BRAF V600E mutation may play in papillary thyroid cancer mortality in a new article in JAMA.

Through a retrospective analysis of more than 1,800 individuals, that research group uncovered a jump in papillary thyroid cancer mortality risk amongst those carrying the mutation.

Finally, researchers from the Mayo Clinic and elsewhere found that mutations in some of the same genes involved in Long QT syndrome may also contribute to a subset of stillbirth cases.

By testing 91 cases of unexplained intrauterine fetal death, focusing on mutations in three Long QT syndrome risk genes, the team found three stillbirth cases involving missense alterations affecting at least one of the Long QT syndrome genes.

Along with an editorial discussing the thyroid cancer research, stillbirth study, and more, today's JAMA issue contains viewpoint articles touching on a range of issues related to the use of genomics in clinical care — from feasibility and financing to its interpretation and standardization.