Stories about: Joel Hirschhorn

News note: GIANT study homes in on obesity genes

obesity genes
Illustration: Elena Hartley

Yes, some obesity is due to genetics. The largest and most powerful study to date has pinned down 14 variants in 13 genes that carry variations associated with body mass index. They provide new clues as to why some people tend to gain weight and have more trouble losing it. Eight of the variants were in genes not previously tied to human obesity.

The study, published last month, was conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium, an international collaboration involving more than 250 research institutions — the same group that brought us height-related genes last year. It combined genetic data from more than 700,000 people and 125 different studies to find rare or low-frequency genetic variants that tracked with obesity.

The study focused on rarer variants in the coding portions of genes, which helped pinpoint causal genes and also helped discover variants with larger effects that those previously discovered by the GIANT consortium. For example, carriers of a variant in the gene MC4R (which produces a protein that tells the brain to stop eating and to burn more energy) weigh 15 pounds more, on average, than people without the variant.

Computational analysis provided some interesting insights into what the 13 genes do. Some, for example, play a role in brain pathways that affect food intake, hunger and satiety. Other variants affect fat-cell biology and how cells expend energy.

This study provided an important confirmation of the role of the nervous system in body weight regulation,” says Joel Hirschhorn MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard, who co-led the study with Ruth Loos, PhD, of the Icahn School of Medicine at Mount Sinai. “Many of the genes from this study were not known to be associated with obesity, but our computational analysis independently implicates these new genes in strikingly similar neuronal pathways as the genes that emerged from our previous work. In addition, our approach newly highlighted a role for genes known to be important in ‘brown fat,’ a type of fat that burns energy and may help keep people lean.”

The researchers think the new findings could help focus the search for new therapeutic targets in obesity.  Read more in Nature Genetics and this press release from Mount Sinai.

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News Note: More evidence that high-glycemic diets cause obesity

a high-glycemic diet

A large genetic analysis lends credence to the idea that insulin spikes after eating high-glycemic foods promote weight gain. People genetically predisposed to produce higher than normal levels of insulin after eating processed carbohydrates — “bad carbs” like white bread, potatoes and refined sugar — were more likely to be obese, the study found.

The researchers, led by David Ludwig, MD, PhD, of Boston Children’s Hospital, Joel Hirschhorn, MD, PhD, of Boston Children’s and the Broad Institute, and Jose Florez, MD, PhD, of the Broad Institute and Massachusetts General Hospital, tapped a collection of large-scale genome-wide association studies. Analyzing data from more than 26,000 people who had glucose challenges, they identified genetic variants linked with high insulin levels 30 minutes after the challenge.

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Making leaps and bounds in 10 years of genome-wide association studies

A Broad Institute cartoon explains what SNPs have to do with genome-wide association studies
A clip from a Broad Institute infographic explains what researchers look for during genome-wide association studies. Download full infographic here. Credit: Susanna Hamilton/Karen Zusi of the Broad Institute.

In 2007, when the first genome-wide association studies (GWAS) got underway, researchers began to realize just how poorly they had previously been able to predict which genes might be related to certain diseases.

“I think we were all surprised how bad our candidate gene lists were,” said Joel Hirschhorn, MD, PhD, in a recent podcast with the Broad Institute of MIT and Harvard. Hirschhorn, a pioneer in GWAS, now leads the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium, which has analyzed the genomes of hundreds of thousands of people over the last several years.

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Why I’m tall and you’re short: GIANT effort finds rare, potent height genes

height genes that make us tall or short

Height is the “poster child” of complex genetic traits, meaning that it’s influenced by multiple genetic variants working together. Because height is easy to measure, it’s a relatively simple model for understanding traits produced by not one gene, but many.

“Mastering the complex genetics of height may give us a blueprint for studying multifactorial disorders that have eluded our complete understanding, such as diabetes and heart disease,” says Joel Hirschhorn, MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard.

Hirschhorn chairs the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, an international group that’s just probed more deeply into the genetics of height than ever before. Its findings, reported today in Nature, reveal previously unknown biological pathways tied to height.

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