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Exome Sequencing Data Links ADCY3 to Severe Obesity

NEW YORK (GenomeWeb) – Loss-of-function mutations in ADCY3 cause severe obesity, according to a series of new studies in Nature Genetics.

Obesity contributes to the deaths of some 2.8 million people a year, and while it is a highly heritable disease, previous genetic studies have only been able to account for a portion of obesity cases.

One of the new studies reported today that whole-exome sequencing uncovered rare variants within the ADCY3 gene in severely obese individuals from both a consanguineous Pakistani population and a European-American family. Another study, meanwhile, linked variants in ADCY3 to an increased risk of both obesity and type 2 diabetes within a Greenlandic population.

"These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity," the University of Lille's Philippe Froguel and the other authors of the first paper wrote of their work.

Froguel and his colleagues sequenced the exomes of 138 people with severe, early-onset obesity and 117 of their family members. These individuals were all from consanguineous families from the Punjab province of Pakistan. Within this cohort, they uncovered four severely obese children from three unrelated families with new or rare variants in ADCY3.

The researchers separately sequenced the exome of a child from a non-consanguineous family of European-American ancestry with severe obesity, and found a compound heterozygous mutation affecting ADCY3.

All these mutated sites in ADYC3 are highly conserved, the researchers noted, suggesting that they have evolutionary significance. ADYC3 belongs to a family of cyclases that catalyze the synthesis of cyclic AMP from ATP. Each of the mutations is predicted to affect the function of the ADYC3 protein, either by being a loss-of-function mutation or by affecting the protein's conformation, the researchers reported.

In addition, Froguel and his colleagues found that mice lacking ADYC3 had an increased appetite and became obese. They also noted that selective ablation of ADYC3 in the mouse brain — the gene is expressed in the hypothalamus — also led to an increase in body fat mass. Further, mice with gain-of-function ADYC3 mutations have less body fat than wild-type mice and are resistant to obesity when fed a high-fat diet.

In the second paper, University of Copenhagen researchers particularly screened for loss-of-function variants associated with obesity within a cohort of Greenlanders. Within this group, they linked an ADYC3 variant that's predicted to eliminate a splice-acceptor site with obesity. Copenhagen's Torben Hansen and his colleagues further searched for this variant among a wider portion of Greenlanders, and found that it has a minor allele frequency of 2.3 percent in the study population.

They uncovered seven individuals who were homozygous for the variant and noted that they had BMIs that were 7.3 kilograms per meter squared higher than the rest of the study population. In addition, three of those seven individuals had type 2 diabetes, one had impaired glucose tolerance, and one had impaired fasting glucose.

Homozygous carriers of the variant Hansen and his colleagues found weren't present in a number of genomic databases, including the non-Greenlandic individuals in the Genome Aggregation Database Consortium and the GoT2D, T2DGenes, SIGMA, LuCAMP, and gnomAD datasets. However, they did find other, rare predicted loss-of-function variants in ADYC3 as well as a heterozygous form of the mutation. The heterozygous carriers, the researchers noted, also had an elevated level of type 2 diabetes.

ADYC3, the Copenhagen team noted, could present a treatment target for obesity and type 2 diabetes.

A third study found that the MC4R and ADYC3 proteins colocalize. In particular, the team from the University of California, San Francisco, reported that the two proteins colocalize at the primary cilia of certain neurons in the hypothalamus.

There, the researchers said, the two proteins transduce signals involved in energy homeostasis, and that mutations affecting the two proteins likely contribute to severe obesity by affecting that signaling.