Walters, R.G. et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463, 671-675

Section of Genomic Medicine, Imperial College London, London W12 0NN, UK.
Nature (Impact Factor: 41.46). 02/2010; 463(7281):671-5. DOI: 10.1038/nature08727
Source: PubMed


Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

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Available from: Valérie Malan
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    • "Specific CNVs may affect inflammatory response, immunity, olfactory function, cell proliferation (Schaschl et al, 2009; Young et al, 2008), and consequently clinically important phenotypic variation. CNVs have been associated with a wide variety of health problems or traits, such as autoimmune diseases (Fanciulli et al, 2007), autism (Sebat et al, 2007), schizophrenia (Stefansson et al, 2008; The International Schizophrenia Consortium, 2008), lean body mass (Hai et al, 2011), obesity (Bochukova et al, 2010; Walters et al, 2010), and HIV/AIDS susceptibility (Gonzalez et al, 2005). The same, or similar, CNVs have been observed in more than one study for more than one trait, such as the 16p11.2 "
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    ABSTRACT: Single nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the "missing heritability" might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5,152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genomewide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genomewide (e.g., P=2 × 10(-8) and OR (95% CI)=0.64 (0.54-0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, while others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication.Neuropsychopharmacology accepted article preview online, 27 October 2014. doi:10.1038/npp.2014.290.
    Full-text · Article · Oct 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Next-generation sequencing technologies are currently being used to undertake CNV analysis (Walters et al. 2010) and whole exome sequencing in obese cohorts and populations (Gill et al. 2014). The aim of these studies is to find low-frequency/rare genetic variants, but assessing the potential pathogenicity of those variants remains a major challenge. "
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    ABSTRACT: Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis.
    Preview · Article · Aug 2014 · Mammalian Genome
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    • "We then quantified these CNVs by high fidelity ddPCR to determine whether they are associated with hypertension. As a robust approach, we used the ‘power of extreme’ approach method [16,17] to enrich for rare but potent variants that could explain high BP. "
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    ABSTRACT: Background The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. Methods Using a “power of extreme” approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. Results A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). Conclusions Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.
    Full-text · Article · Jul 2014 · BMC Medical Genomics
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