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Genomics in the Journals: Apr 11, 2013

NEW YORK (GenomeWeb News) – In Nature Genetics, researchers from the Wellcome Trust Sanger Institute and Addenbrooke's Hospital described research aimed at uncovering new genetic contributors to early onset obesity — from fairly common SNPs to far more rare copy number variations.

By focusing their SNP and CNV analyses on children at the extreme end of the body mass index spectrum, investigators reasoned that it might be possible to see both common and lower-frequency variants missed in past obesity studies, including those focused on adult forms of the condition.

Indeed, the team identified dozens of candidate SNPs by comparing genetic profiles in 1,509 severely obese children with those in almost 5,400 controls from the Wellcome Trust Case Control Consortium 2. And follow-up experiments in another 971 affected children pointed to significant ties between severe childhood obesity and variants in four genes.

The study also pointed to rarer genetic alterations with a range of effects on childhood obesity risk, the study's authors said. For instance, they found that obese children are particularly prone to carrying rare copy number variations — including deletions affecting G-protein coupled receptor genes that contribute to neuronal regulation over energy homeostasis.

"Our study adds evidence that a range of both rare and common genetic variants are responsible for severe childhood obesity," Wellcome Trust Sanger Institute researcher Inês Barroso, co-senior author on the study, said in a statement. "This work brings us a step closer to understanding the biology underlying this severe form of childhood obesity and providing a potential diagnosis to the children and their parents."

For another obesity-related study, also appearing in Nature Genetics, a large international team considered the genetics behind multiple anthropomorphic traits — namely, BMI, waist-to-hip ratio, and height — also using an approach focused on individuals at the extreme ends of the trait spectrum.

With a meta-analysis that brought together genotyping data for as many as 168,267 individuals from past studies by those involved in the Genetic Investigation of Anthropometrical Traits consortium, researchers narrowed in on a few hundred suspicious SNPs.

Follow-up tests using data for nearly 110,000 more individuals point to new SNPs in and around four genes that seem to influence height extremes. Seven other new loci were linked to obesity extremes. Even so, the study's authors noted that several known genetic factors falling out of the analyses tended to overlap with those described for more subtle increases or decreases in height and weight.

"Our results suggest that extremely obese individuals have a greater number of gene variants that increase the risk of obesity," senior author Erik Ingelsson, a researcher affiliated with Uppsala University and other centers in Sweden and the UK, said in a statement, "rather than completely different genes being involved."

Liver regeneration appears to be negatively regulated by a kinase enzyme encoded by the MKK4 gene, according to mouse study in Cell. German researchers sent sets of inhibitory small hairpin RNAs into mouse livers to look for genes that enhanced or dampened liver regeneration.

The in vivo screen led to MKK4, which codes for an enzyme that's thought to participate in embryonic liver development and differentiation. And the team's subsequent experiments indicated that MKK4 plays a central role in regulating liver regeneration, too.

For example, liver cells appeared more apt to regenerate when the gene was stably silenced by RNA interference, study authors noted. Similarly, curbing MKK4 activity in mouse models mimicking acute or chronic liver disease led to a boost in liver regeneration, they said, hinting that the gene might serve as a useful therapeutic target in diseases that dampen the liver's regenerative abilities.

"It is now conceivable to develop specific pharmacological inhibitors of MKK4 in order to treat patients with liver disease," the University of Tübingen's Lars Zender, senior author on the study, said in a statement.

"Such treatment strategies are urgently needed in the clinic," he continued, "as currently the only curative treatment option for patients with end-stage liver disease is liver transplantation, and the number of donors is limited."

An international team led by investigators in the US and France found evidence that individuals born without a spleen because of a rare condition called isolated congenital asplenia, or ICA, tend to harbor haploinsufficiency-causing mutations in the ribosomal protein-coding gene RPSA.

As they reported in an early, online edition of Science study, the researchers performed exome sequencing on a single representative per family from nearly two-dozen ICA-affected families. By comparing suspicious mutations in these protein-coding sequences with variants found in more than 500 unaffected control exomes, they eventually narrowed in on RPSA — a ribosomal subunit gene harboring non-synonymous mutations in eight of the 23 families.

Targeted RPSA sequencing in all 33 affected individuals from the original 23 families unearthed even more ICA-associated mutations in the gene. All told, the study's authors found 18 ICA-affected individuals with frameshift, nonsense, or missense mutations predicted to staunch the activity of one RPSA allele.

"We do not yet understand the pathogenesis of ICA," they wrote. As such, they said, RPSA's apparent role in spleen development "calls for explorations of the underlying mechanisms."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.