Publications
193 results found
Li Y, Zheng H, Luo R, et al., 2011, Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly, Nat Biotechnol, Vol: 29, Pages: 723-730, ISSN: 1546-1696
Here we use whole-genome de novo assembly of second-generation sequencing reads to map structural variation (SV) in an Asian genome and an African genome. Our approach identifies small- and intermediate-size homozygous variants (1-50 kb) including insertions, deletions, inversions and their precise breakpoints, and in contrast to other methods, can resolve complex rearrangements. In total, we identified 277,243 SVs ranging in length from 1-23 kb. Validation using computational and experimental methods suggests that we achieve overall <6% false-positive rate and <10% false-negative rate in genomic regions that can be assembled, which outperforms other methods. Analysis of the SVs in the genomes of 106 individuals sequenced as part of the 1000 Genomes Project suggests that SVs account for a greater fraction of the diversity between individuals than do single-nucleotide polymorphisms (SNPs). These findings demonstrate that whole-genome de novo assembly is a feasible approach to deriving more comprehensive maps of genetic variation.
Jacquemont S, Reymond A, Zufferey F, et al., 2011, Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus, Nature, Vol: 478, Pages: 97-102, ISSN: 1476-4687
Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) </= 18.5 kg per m(2) in adults and </= -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a approximately 600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiolog
de Smith AJ, van Haelst MM, Ellis RJ, et al., 2011, Chromosome 19p13.3 deletion in a patient with macrocephaly, obesity, mental retardation, and behavior problems, Am J Med Genet A, Vol: 155A, Pages: 1192-1195, ISSN: 1552-4833
Fernando MM, de Smith AJ, Coin L, et al., 2011, Investigation of the HIN200 locus in UK SLE families identifies novel copy number variants, Ann Hum Genet, Vol: 75, Pages: 383-397, ISSN: 1469-1809
We undertook a candidate locus study of the HIN200 gene cluster on 1q21-23 in UK systemic lupus erythematosus (SLE) families. To date, despite mounting evidence demonstrating the importance of these proteins in autoimmune disease, cancer, apoptosis, inflammation, and cell cycle arrest, there has been a dearth of data with respect to the genetic characterisation of the HIN200 locus in SLE or any other disease. We typed 83 single nucleotide polymorphisms (SNPs) across 317 kb of the HIN200 cluster in 428 UK SLE families and sought replication from a European-American lupus cohort. We do not find strong evidence of SNP association in either cohort. Interestingly, we do observe a trend for association with certain HIN200 SNPs and serologic subphenotypes in UK SLE that parallels the association of lupus antibodies with the orthologous murine locus. Furthermore, we find the HIN200 locus to be unexpectedly complex in terms of genetic structural organisation. We have identified a number of copy number variants (CNVs) in this region in healthy French males, HapMap samples, and UK SLE families. In summary, candidate interferon signalling genes show evidence of common CNV in human SLE and healthy subjects. The impact of these CNVs in health and disease remains to be determined.
Buxton JL, Walters RG, Visvikis-Siest S, et al., 2011, Childhood obesity is associated with shorter leukocyte telomere length, J Clin Endocrinol Metab, Vol: 96, Pages: 1500-1505, ISSN: 1945-7197
CONTEXT: Obesity in adults is associated with shorter mean leukocyte telomere length (LTL), a marker of biological age that is also associated with age-related conditions including cardiovascular disease and type 2 diabetes. However, studies of childhood obesity and LTL have proved inconclusive. OBJECTIVE: The objective of the study was to clarify the relationship between telomere length and childhood obesity by measuring the average LTL in a large case-control cohort. PARTICIPANTS AND METHODS: LTL was measured in 793 French children aged 2-17 yr (471 with early onset obesity and 322 nonobese controls) using multiplex quantitative real-time PCR. The average LTL in the two groups was compared, and the relationships between telomere length and selected anthropometric and biochemical measurements were examined. RESULTS: Obese children had a mean LTL that was 23.9% shorter than that of nonobese children (P < 0.0001). Telomere length was inversely associated with age (R = -0.17, P = 0.002 in controls; R = -0.15, P = 0.001 in cases), log weight (R= -0.13, P = 0.017 in controls; R = -0.16, P = 0.0004 in cases), and height (R = -0.15, P = 0.008 in controls; R = -0.17, P = 0.0002 in cases). The mean LTL of girls and boys was not significantly different in either the cases or controls or in the group overall. CONCLUSION: Obese girls and boys have significantly shorter leukocyte telomeres than their nonobese counterparts, a finding that highlights a potentially deleterious impact of early onset obesity on future health.
Trewick AL, Moustafa JS, de Smith AJ, et al., 2011, Accurate single-nucleotide polymorphism allele assignment in trisomic or duplicated regions by using a single base-extension assay with MALDI-TOF mass spectrometry, Clin Chem, Vol: 57, Pages: 1188-1195, ISSN: 1530-8561
BACKGROUND: The accurate assignment of alleles embedded within trisomic or duplicated regions is an essential prerequisite for assessing the combined effects of single-nucleotide polymorphisms (SNPs) and genomic copy number. Such an integrated analysis is challenging because heterozygotes for such a SNP may be one of 2 genotypes-AAB or ABB. Established methods for SNP genotyping, however, can have difficulty discriminating between the 2 heterozygous trisomic genotypes. We developed a method for assigning heterozygous trisomic genotypes that uses the ratio of the height of the 2 allele peaks obtained by mass spectrometry after a single-base extension assay. METHODS: Eighteen COL6A2 (collagen, type VI, alpha 2) SNPs were analyzed in euploid and trisomic individuals by means of a multiplexed single-base extension assay that generated allele-specific oligonucleotides of differing M(r) values for detection by MALDI-TOF mass spectrometry. Reference data (mean and SD) for the allele peak height ratios were determined from heterozygous euploid samples. The heterozygous trisomic genotypes were assigned by calculating the z score for each trisomic allele peak height ratio and by considering the sign (+/-) of the z score. RESULTS: Heterozygous trisomic genotypes were assigned in 96.1% (range, 89.9%-100%) of the samples for each SNP analyzed. The genotypes obtained were reproduced in 95 (97.5%) of 97 loci retested in a second assay. Subsequently, the origin of nondisjunction was determined in 108 (82%) of 132 family trios with a Down syndrome child. CONCLUSIONS: This approach enabled reliable genotyping of heterozygous trisomic samples and the determination of the origin of nondisjunction in Down syndrome family trios.
Al-Hassi HO, Murugananthan A, Bernardo DO, et al., 2010, CCR7-induced homing of human gut dendritic cells mediated by LepRb; differences between ileum and colon and in Crohn's disease, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 161-162, ISSN: 0019-2805
Speliotes EK, Willer CJ, Berndt SI, et al., 2010, Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index, Nature Genetics, Vol: 42, Pages: 937-948, ISSN: 1546-1718
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Blakemore A, 2010, New approaches to the molecular dissection of human obesity, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S21-S21, ISSN: 0022-2593
Price CL, Hassi HO, English NR, et al., 2010, Methylglyoxal modulates immune responses: relevance to diabetes, Journal of Cellular and Molecular Medicine, Vol: 14, Pages: 1806-1815, ISSN: 1582-1838
Increased methylglyoxal (MG) concentrations and formation of advanced glycation end-products (AGEs) are major pathways of glycaemic damage in diabetes, leading to vascular and neuronal complications. Diabetes patients also suffer increased susceptibility to many common infections, the underlying causes of which remain elusive. We hypothesized that immune glycation damage may account for this increased susceptibility. We previously showed that the reaction mixture (RM) for MG glycation of peptide blocks up regulation of CD83 in myeloid cells and inhibits primary stimulation of T cells. Here, we continue to investigate immune glycation damage, assessing surface and intracellular cytokine protein expression by flow cytometry, T-cell proliferation using a carboxyfluorescein succinimidyl ester assay, and mRNA levels by RT-PCR. We show that the immunomodulatory component of this RM was MG itself, with MG alone causing equivalent block of CD83 and loss of primary stimulation. Block of CD83 expression could be reversed by MG scavenger N-acetyl cysteine. Further, MG within RM inhibited stimulated production of interleukin (IL)-10 protein from myeloid cells plus interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha from T cells. Loss of IL-10 and IFN-gamma was confirmed by RT-PCR analysis of mRNA, while TNF-alpha message was raised. Loss of TNF-alpha protein was also shown by ELISA of culture supernatants. In addition, MG reduced major histocompatibility complex (MHC) class I expression on the surface of myeloid cells and increased their propensity to apoptose. We conclude that MG is a potent suppressor of myeloid and T-cell immune function and may be a major player in diabetes-associated susceptibility to infection.
Diskin SJ, Bosse K, Mayes PA, et al., 2010, Identification of <i>NME7</i> as a predisposition locus and candidate oncogene in neuroblastoma, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Walters RG, Jacquemont S, Valsesia A, et al., 2010, A new highly penetrant form of obesity due to deletions on chromosome 16p11.2, Nature, Vol: 463, Pages: 671-675, ISSN: 1476-4687
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.
de Smith AJ, Trewick AL, Blakemore AI, 2010, Implications of copy number variation in people with chromosomal abnormalities: potential for greater variation in copy number state may contribute to variability of phenotype, HUGO J, Vol: 4
Coin LJ, Asher JE, Walters RG, et al., 2010, cnvHap: an integrative population and haplotype-based multiplatform model of SNPs and CNVs, Nat Methods, Vol: 7, Pages: 541-546, ISSN: 1548-7105
Although genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) associated with complex disease, these variants account for a small portion of heritability. Some contribution to this 'missing heritability' may come from copy-number variants (CNVs), in particular rare CNVs; but assessment of this contribution remains challenging because of the difficulty in accurately genotyping CNVs, particularly small variants. We report a population-based approach for the identification of CNVs that integrates data from multiple samples and platforms. Our algorithm, cnvHap, jointly learns a chromosome-wide haplotype model of CNVs and cluster-based models of allele intensity at each probe. Using data for 50 French individuals assayed on four separate platforms, we found that cnvHap correctly detected at least 14% more deleted and 50% more amplified genotypes than PennCNV or QuantiSNP, with an 82% and 115% improvement for aberrations containing <10 probes. Combining data from multiple platforms additionally improved sensitivity.
Su SY, Asher JE, Jarvelin MR, et al., 2010, Inferring combined CNV/SNP haplotypes from genotype data, Bioinformatics, Vol: 26, Pages: 1437-1445, ISSN: 1367-4811
MOTIVATION: Copy number variations (CNVs) are increasingly recognized as an substantial source of individual genetic variation, and hence there is a growing interest in investigating the evolutionary history of CNVs as well as their impact on complex disease susceptibility. CNV/SNP haplotypes are critical for this research, but although many methods have been proposed for inferring integer copy number, few have been designed for inferring CNV haplotypic phase and none of these are applicable at genome-wide scale. Here, we present a method for inferring missing CNV genotypes, predicting CNV allelic configuration and for inferring CNV haplotypic phase from SNP/CNV genotype data. Our method, implemented in the software polyHap v2.0, is based on a hidden Markov model, which models the joint haplotype structure between CNVs and SNPs. Thus, haplotypic phase of CNVs and SNPs are inferred simultaneously. A sampling algorithm is employed to obtain a measure of confidence/credibility of each estimate. RESULTS: We generated diploid phase-known CNV-SNP genotype datasets by pairing male X chromosome CNV-SNP haplotypes. We show that polyHap provides accurate estimates of missing CNV genotypes, allelic configuration and CNV haplotypic phase on these datasets. We applied our method to a non-simulated dataset-a region on Chromosome 2 encompassing a short deletion. The results confirm that polyHap's accuracy extends to real-life datasets. AVAILABILITY: Our method is implemented in version 2.0 of the polyHap software package and can be downloaded from http://www.imperial.ac.uk/medicine/people/l.coin.
Fu Y, Chen Z, Blakemore AI, et al., 2010, Absence of AVPR2 copy number variation in eunatremic and dysnatremic subjects in non-Hispanic Caucasian populations, Physiol Genomics, Vol: 40, Pages: 121-127, ISSN: 1531-2267
Copy number variation (CNV) is increasingly recognized as a source of phenotypic variation among humans. We hypothesized that a CNV in the human arginine vasopressin receptor-2 gene (AVPR2) would be associated with serum sodium concentration based on the following lines of evidence: 1) the protein product of the AVPR2 gene is essential for renal water conservation; 2) mutations in the AVPR2 gene are associated with aberrant water balance in humans; 3) heritability of serum sodium concentration may be greater in females than in males; 4) the AVPR2 gene is X-linked; and 5) a common CNV spanning the AVPR2 gene was recently described in a non-Hispanic Caucasian population. We developed a highly reproducible assay for AVPR2 CNV. Among 279 subjects with measured serum sodium concentration in the Offspring Cohort of the Framingham Heart Study, no subjects exhibited CNV at the AVPR2 locus. Among 517 subjects in the Osteoporotic Fractures in Men Study (MrOS)-including 152 with hyponatremia and 183 with hypernatremia-no subjects with CNV at the AVPR2 locus were identified. CNV at the AVPR2 locus could not be independently confirmed, and CNV at the AVPR2 gene is unlikely to influence systemic water balance on a population-wide basis in non-Hispanic Caucasian subjects. A novel AVPR2 single nucleotide polymorphism affecting the reporter hybridization site gave rise to an artifactually low copy number signal (i.e., less than unity) in one male African American subject. Reanalysis of the original comparative genomic hybridization data revealed bona fide CNVs flanking-but not incorporating-the AVPR2 gene, consistent with our new genotyping data.
Blakemore AI, Froguel P, 2010, Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine, Ann N Y Acad Sci, Vol: 1214, Pages: 180-189, ISSN: 1749-6632
Mendelian forms of obesity are already known to account for approximately 5% of the severely obese but are currently underinvestigated. In contrast, there has been much recent concentration on genome-wide single nucleotide polymorphism (SNP) associations in obesity, with particular emphasis given to the role of the fat mass and obesity associated (FTO) gene. Unfortunately, despite the enormous resources devoted to this work, none of the SNP markers in the approximately 30 genes discovered to have associations with common obesity have meaningful predictive power. This is very different from the situation for Mendelian obesity, where mutations have very clear effects on phenotype. Study of Mendelian obesity has also added significantly to our understanding of mechanisms of appetite regulation, with all known causative genes being active in the brain and most forming part of the leptin-melanocortin signaling pathway. Investigation of genomic structural variation has also recently revealed deletions causing obesity, sometimes with concomitant neurocognitive dysfunction. Advances in next-generation sequencing are expected to uncover additional highly penetrant causes of obesity. Screening for Mendelian forms of obesity is rarely carried out but holds considerable promise for improved clinical care of these high-risk patients.
Blakemore A, Froguel P, 2009, Obesity: Are genes responsible?, Diabetes and Primary Care, Vol: 11, ISSN: 1466-8955
Clark D, Skrobot OA, Adebiyi I, et al., 2009, Apolipoprotein-E gene variants associated with cardiovascular risk factors in antipsychotic recipients, EUROPEAN PSYCHIATRY, Vol: 24, Pages: 456-463, ISSN: 0924-9338
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Moustafa JSE-S, Coin LJM, de Smith AJ, et al., 2009, CNVs in Obesity: Uncovering a New Level of Genomic Variation, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S91-S91, ISSN: 0022-2593
de Smith AJ, Purmann C, Walters RG, et al., 2009, Elucidating the aetiology of Prader-Willi syndrome: deletion of the HBII-85 class of snoRNA is associated with hyperphagia, obesity and hypogonadism, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S83-S83, ISSN: 0022-2593
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Trewick AL, Froguel P, Coin LJM, et al., 2009, Assignment of trisomic genotypes using the Sequenom iPLEX MALDI TOF assay reveals transmission disequilibrium of two SNP loci in the Type VI Collagen gene cluster associated with CHD in Down's Syndrome., British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S92-S92, ISSN: 0022-2593
Asher J, Walley AJ, Froguel P, et al., 2009, Genes in the ACAD family show preliminary evidence of association with polygenic obesity, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S89-S89, ISSN: 0022-2593
Buxton J, Coin LJM, Walters RG, et al., 2009, Identification and validation of novel genomic CNVs associated with Type 2 diabetes, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S93-S93, ISSN: 0022-2593
Blakemore A, de Smith A, 2009, CNV in Down Syndrome heart conditions, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S22-S22, ISSN: 0022-2593
Diskin SJ, Hou C, Glessner JT, et al., 2009, Copy number variation at 1q21.1 associated with neuroblastoma, Nature, Vol: 459, Pages: 987-991, ISSN: 1476-4687
Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.
Blakemore AI, Meyre D, Delplanque J, et al., 2009, A rare variant in the visfatin gene (NAMPT/PBEF1) is associated with protection from obesity, Obesity (Silver Spring), Vol: 17, Pages: 1549-1553, ISSN: 1930-7381
Visfatin was recently reported as a novel adipokine encoded by the NAMPT (PBEF1) gene. This study was aimed at investigation of the possibility that single-nucleotide polymorphisms (SNPs) in the visfatin gene are associated with either obesity or type 2 diabetes (T2D). A set of eight "tag-SNPs" were selected and ABI SNPlex assays designed for genotyping purposes. A total of 1,709 severely obese subjects were typed (896 class III obese adults and 813 children) together with 2,367 T2D individuals and 2,850 controls. For quantitative trait analysis, an additional 2,362 subjects were typed for rs10487818 from a general population sample. One rare SNP, rs10487818, located in intron 4 of NAMPT was associated with severe obesity, with a minor allele frequency of 1.6% in controls, 0.4% in the class III obese adults and, remarkably, 0% in the severely obese children. A highly significant association was observed for the presence or absence of the rare allele, i.e., (A,A) vs. (A,T + T,T) genotypes, in children (P = 6 x 10(-9)) and in adults (P = 8 x 10(-5)). No other significant (P < 0.05) association was observed with obesity or T2D for this or any other SNP. No association with BMI or waist-to-hip ratio was observed in a general population sample (n = 5,212). This is one of the first rare SNPs shown to be protective against a common polygenic disease and provides further evidence that rare alleles of strong effect can contribute to complex diseases such as severe obesity.
Cauchi S, Stutzmann F, Cavalcanti-Proenca C, et al., 2009, Combined effects of MC4R and FTO common genetic variants on obesity in European general populations, J Mol Med, Vol: 87, Pages: 537-546, ISSN: 1432-1440
Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (approximately 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined eff
Meyre D, Delplanque J, Chevre JC, et al., 2009, Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations, Nat Genet, Vol: 41, Pages: 157-159, ISSN: 1546-1718
We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).
Blakemore AI, Froguel P, 2009, Obesity: are genes to blame?, Diabetes and Primary Care, Vol: 11, Pages: 4-5
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