BADERC-Zhijun Luo

Richa Saxena, PhD

Circadian/sleep dysfunction and risk of type 2 diabetes

The Saxena laboratory studies the mechanisms by which variation in sleep and circadian pathway genes leads to increased risk for type 2 diabetes in humans.

Through genome-wide association studies in the MAGIC consortium, we have found that variants in a melatonin receptor (MTNR1B) and a core circadian clock gene, cryptochrome 2 (CRY2) lower fasting glucose levels, reduce insulin secretion and increase risk of T2D.

Compelling evidence is emerging on the importance of circadian regulation in type 2 diabetes. Epidemiologic data indicate that inadequate sleep duration, compromised sleep quality and shift work each increase the risk for future weight gain, type 2 diabetes (T2D) and cardiovascular disease, and experimental studies in humans demonstrate that acute sleep restriction and circadian misalignment affect glucose metabolism. In collaboration with researchers at the Division of Sleep Medicine at the Brigham and Women’s Hospital, we are exploring the mechanistic links between sleep/circadian dysfunction and type 2 diabetes pathogenesis.

Our goals are:

To identify causal variants and genes in T2D loci harboring sleep and circadian genes
To understand the mechanism by which causal T2D risk variants alter sleep, circadian and metabolic physiology
To discover more sleep and circadian gene variants that influence metabolic disease onset, progression or response to therapy

We use human genetic approaches including large-scale GWAS and next generation sequencing to map new disease loci and understand human physiology, as well as molecular genetics, genomics and cell culture models for functional characterization of disease genes.

Genetics of Pre-eclampsia
Preeclampsia is a common pregnancy disorder and associated with future increased risk of cardiovascular disease. In collaboration with researchers at BIDMC and the Danish National Birth Cohort, we are using large-scale sequencing approaches to search for genetic factors that contribute to risk of preeclampsia.

References:

Saxena R*, Hivert MF* et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010;42:142-8.
Dupuis J*, Langenberg C*, Prokopenko I*, Saxena R*, Soranzo N* et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42:105-16.
Prokopenko I*, Langenberg C*, Florez JC*, Saxena R*, Soranzo N* et al. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nat Genet 2009;41:77-81.
Lyssenko V, Nagorny CLF, Erdos MR, Wierup N, Jonsson A, Spegel P, Bugliani M. Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe R, Mulder H and Groop L A common variant in the melatonin receptor gene (MTNR1B) is associated with increased risk of future type 2 diabetes and impaired early insulin secretion Nat Genet 2009;41:82-8.
Zeggini E*, Scott LJ*, Saxena R*, Voight B* for the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. Meta-analysis of genome-wide association data and large-scale replication identifies several additional susceptibility loci for type 2 diabetes. Nat Genet 2008;40:638-45.
The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336.*RS led writing, study design & phenotype groups.
Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, Lindblad U, Daly MJ, Tuomi T, Hirschhorn JN, Ardlie KG, Groop LC, Altshuler D. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006;55:2890-5.
Saxena R, de Bakker PIW, Singer K, Mootha VK, Burtt N, Hirschhorn JN, Gaudet F, Isomaa B, Daly MJ, Groop L, Ardlie KG, and Altshuler D. Comprehensive association testing of common mitochondrial DNA variation in metabolic Disease. Am J of Hum Genet 2006;79:54-61.

* Equal contribution






			Richa Saxena, PhD Circadian/sleep dysfunction and risk of type 2 diabetes The Saxena laboratory studies the mechanisms by which variation in sleep and circadian pathway genes leads to increased risk for type 2 diabetes in humans. Through genome-wide association studies in the MAGIC consortium, we have found that variants in a melatonin receptor (MTNR1B) and a core circadian clock gene, cryptochrome 2 (CRY2) lower fasting glucose levels, reduce insulin secretion and increase risk of T2D. Compelling evidence is emerging on the importance of circadian regulation in type 2 diabetes. Epidemiologic data indicate that inadequate sleep duration, compromised sleep quality and shift work each increase the risk for future weight gain, type 2 diabetes (T2D) and cardiovascular disease, and experimental studies in humans demonstrate that acute sleep restriction and circadian misalignment affect glucose metabolism. In collaboration with researchers at the Division of Sleep Medicine at the Brigham and Women’s Hospital, we are exploring the mechanistic links between sleep/circadian dysfunction and type 2 diabetes pathogenesis. Our goals are: To identify causal variants and genes in T2D loci harboring sleep and circadian genes To understand the mechanism by which causal T2D risk variants alter sleep, circadian and metabolic physiology To discover more sleep and circadian gene variants that influence metabolic disease onset, progression or response to therapy We use human genetic approaches including large-scale GWAS and next generation sequencing to map new disease loci and understand human physiology, as well as molecular genetics, genomics and cell culture models for functional characterization of disease genes. Genetics of Pre-eclampsia Preeclampsia is a common pregnancy disorder and associated with future increased risk of cardiovascular disease. In collaboration with researchers at BIDMC and the Danish National Birth Cohort, we are using large-scale sequencing approaches to search for genetic factors that contribute to risk of preeclampsia. References: Saxena R, Hivert MF et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010;42:142-8. Dupuis J, Langenberg C, Prokopenko I, Saxena R*, Soranzo N et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42:105-16. Prokopenko I, Langenberg C, Florez JC, Saxena R*, Soranzo N et al. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nat Genet 2009;41:77-81. Lyssenko V, Nagorny CLF, Erdos MR, Wierup N, Jonsson A, Spegel P, Bugliani M. Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe R, Mulder H and Groop L A common variant in the melatonin receptor gene (MTNR1B) is associated with increased risk of future type 2 diabetes and impaired early insulin secretion Nat Genet 2009;41:82-8. Zeggini E, Scott LJ, Saxena R, Voight B for the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. Meta-analysis of genome-wide association data and large-scale replication identifies several additional susceptibility loci for type 2 diabetes. Nat Genet 2008;40:638-45. The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336.RS led writing, study design & phenotype groups. Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, Lindblad U, Daly MJ, Tuomi T, Hirschhorn JN, Ardlie KG, Groop LC, Altshuler D. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006;55:2890-5. Saxena R, de Bakker PIW, Singer K, Mootha VK, Burtt N, Hirschhorn JN, Gaudet F, Isomaa B, Daly MJ, Groop L, Ardlie KG, and Altshuler D. Comprehensive association testing of common mitochondrial DNA variation in metabolic Disease. Am J of Hum Genet 2006;79:54-61. Equal contribution