Variants in the ADCY3 gene, plus the contributing effects of MC4R, as a cause of obesity

Obesity, defined as a body mass index (BMI) of >30 kg/m2, is commonly used in these GEITP pages as an example of a multifactorial trait –– i.e. a reflection of hundreds if not thousands of “small-effect” genes, plus epigenetic factors, plus environmental effects (e.g. diet, lack of exercise). Response to a drug (efficacy vs toxicity) or an environmental toxicant (toxicity) are also often a multifactorial trait. However, both obesity and response to a drug or environmental toxicant can be manifested by a “large-effect” gene. The three (seemingly unrelated) full-length papers [attached] provide an example of such a large-effect gene.

Scientists in the first report were studying (in a Greenland population) a type-2 diabetes (T2D)–associated gene and inadvertently found a single-nucleotide variant (SNV) disrupting the ADCY3 gene, which encodes adenylate cyclase-3. This variant had a minor allele frequency of 2.3% in the Greenlandic cohort (3.1% in those of Inuit ancestry), but was absent in >138,000 non-Greenlandic individuals studied. Their data supported a recessive model of inheritance (similar to the phenotype of blue eye color). Individuals homozygous for the variant (having two copies of the mutant allele, i.e. one in each gene on the chromosome pair) had a higher BMI (7.3 kg/ m2 higher on average) and increased risk of T2D.

Authors in the second report describe the identification of obesity-caused mutations in ADCY3, while focusing initially on a cohort of severely obese consanguineous individuals (offspring derived from the same ancestor; e.g. first-cousin marriage) from Pakistan, and subsequently in a severely obese European-American child. Functional follow-up studies showed that three of the SNVs decreased ADCY3 catalytic activity –– providing further support for the causal role in obesity.

Scientists in the third report were studying mutations in genes encoding cilia proteins (cilia are hairlike structures present in many different cell types; in fact, even in microorganisms) that have a critical role in signaling pathways. Authors demonstrated the co-localization of MC4R (melanocortin-4 receptor) and ADCY3 to primary cilia in a subset of hypothalamic neurons; they further showed MC4R obesity-causing mutations could impair MC4R ciliary localization in these cells and in intact mouse brain. Specific inhibition of ADCY3 activity at primary cilia of MC4R-expressing neurons was sufficient to cause obesity in mice, confirming the essential role of MC4R and ADCY3 at primary neuronal cilia in regulating body weight..!! Their data reveal a common pathway for obesity caused by cilia-related genes and obesity associated with mutations in leptin–melanocortin pathway genes.

This combination of three very different studies is a great example of different research groups stumbling upon a common large-effect gene, variants in which are one cause of obesity. And the third paper even links the ADCY3 gene to the hypothalamic leptin–melanocortin pathway –– which is well known to participate in altering food intake, energy expenditure, and neuroendocrine-function..!!

Nature Genet Feb 2o18; 50: 175-179 & 180–185 & 172–174 & News-N-Views editorial 166–167

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