Dataset Information

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

ABSTRACT: 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.

SUBMITTER: Walters RG

PROVIDER: S-EPMC2880448 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Walters R G RG Jacquemont S S Valsesia A A de Smith A J AJ Martinet D D Andersson J J Falchi M M Chen F F Andrieux J J Lobbens S S Delobel B B Stutzmann F F El-Sayed Moustafa J S JS Chèvre J-C JC Lecoeur C C Vatin V V Bouquillon S S Buxton J L JL Boute O O Holder-Espinasse M M Cuisset J-M JM Lemaitre M-P MP Ambresin A-E AE Brioschi A A Gaillard M M Giusti V V Fellmann F F Ferrarini A A Hadjikhani N N Campion D D Guilmatre A A Goldenberg A A Calmels N N Mandel J-L JL Le Caignec C C David A A Isidor B B Cordier M-P MP Dupuis-Girod S S Labalme A A Sanlaville D D Béri-Dexheimer M M Jonveaux P P Leheup B B Ounap K K Bochukova E G EG Henning E E Keogh J J Ellis R J RJ Macdermot K D KD van Haelst M M MM Vincent-Delorme C C Plessis G G Touraine R R Philippe A A Malan V V Mathieu-Dramard M M Chiesa J J Blaumeiser B B Kooy R F RF Caiazzo R R Pigeyre M M Balkau B B Sladek R R Bergmann S S Mooser V V Waterworth D D Reymond A A Vollenweider P P Waeber G G Kurg A A Palta P P Esko T T Metspalu A A Nelis M M Elliott P P Hartikainen A-L AL McCarthy M I MI Peltonen L L Carlsson L L Jacobson P P Sjöström L L Huang N N Hurles M E ME O'Rahilly S S Farooqi I S IS Männik K K Jarvelin M-R MR Pattou F F Meyre D D Walley A J AJ Coin L J M LJ Blakemore A I F AI Froguel P P Beckmann J S JS

Nature 20100201 7281

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 w ...[more]

PMID: 20130649

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Project description:BackgroundLp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype.MethodsA large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed.ResultsSeventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the LPA locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant LPA single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the LPA locus was omitted.ConclusionsHigh-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals, LPA can be a major locus driving a very high CAD GRS. This underpins the large contribution of the LPA locus to the cardiovascular genetic risk in families.

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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Publications

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

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