Prof Cecilia Lindgren

Research Area: Genetics and Genomics
Technology Exchange: Bioinformatics, Computational biology, SNP typing and Statistical genetics
Keywords: obesity, fat distribution, meta-analysis, genetic association and gene expression
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Obesity and its consequences are major and growing challenges for health care worldwide. Recently, the first common variants have been identified which influence overall levels of adiposity and predispose to obesity at the population level: these findings should lead to improved understanding of the mechanisms involved in the regulation of overall energy balance. However, not all obese individuals are equally vulnerable to diabetes, insulin resistance and the other adverse consequences of obesity, and it has long been appreciated that the distribution of fat (particularly the degree of central or visceral obesity) is an additional and independent determinant of individual risk of metabolic and cardiovascular disease.

Our research seeks to advance understanding of the mechanisms involved in obesity and the regulation of differential central fat accumulation in the belief that an appreciation of these mechanisms will complement advances in understanding of overall energy balance.

By applying a range of genetic and genomic approaches, we expect to identify genetic variants influencing regional fat distribution, and to illuminate some of the biological pathways involved. Our specific objectives are:

  1. To undertake identification of genetic variants influencing obesity and individual patterns of fat distribution and central obesity through large-scale genome-wide association meta-analysis and fine-mapping;
  2. To examine the relationships between sequence variation, expression of mRNA, microRNAs and molecular and physiological phenotypes, in human adipose samples, to identify adipose-specific pathways relevant to individual differences in obesity and central fat distribution;
  3. To follow-up of the key findings from genetic, epidemiological and functional perspectives.

This knowledge should support translational advances in the management of obesity through development of novel diagnostic and therapeutic options.

There are no collaborations listed for this principal investigator.

Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM et al. 2008. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet, 40 (6), pp. 768-775. Read abstract | Read more

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits. Hide abstract

Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR et al. 2008. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet, 40 (5), pp. 575-583. Read abstract | Read more

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. Hide abstract

Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR et al. 2007. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science, 316 (5829), pp. 1336-1341. Read abstract | Read more

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. Hide abstract

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS et al. 2007. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science, 316 (5826), pp. 889-894. Read abstract | Read more

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass. Hide abstract

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E et al. 2003. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet, 34 (3), pp. 267-273. Read abstract | Read more

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments. Hide abstract

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