Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity

Wheeler, Eleanor; Huang, Ni; Bochukova, Elena G.; Keogh, Julia M.; Lindsay, Sarah; Garg, Shivam; Henning, Elana; Blackburn, Hannah; Loos, Ruth J.F.; Wareham, Nick; O’Rahilly, Stephen; Hurles, Matthew E.; Barroso, Inês; Farooqi, I. Sadaf

doi:10.1038/ng.2607

Cited by 287 publications

(221 citation statements)

References 26 publications

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“…The mechanisms by which CNVs can affect gene expression and phenotypic traits include alteration of gene dosage and disruption of coding sequences or regulatory elements (Feuk et al ., 2006b). CNVs have been implicated in numerous diseases and complex traits, like schizophrenia (International Schizophrenia C, 2008), autism (Marshall et al ., 2008), and obesity (Wheeler et al ., 2013), but only a few studies have addressed the role of CNVs in survival and longevity.…”

Section: Introductionmentioning

confidence: 99%

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

et al. 2015

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SummaryCopy number variants (CNVs) represent a significant source of genetic variation in the human genome and have been implicated in numerous diseases and complex traits. To date, only a few studies have investigated the role of CNVs in human lifespan. To investigate the impact of CNVs on prospective mortality at the extreme end of life, where the genetic component of lifespan appears most profound, we analyzed genomewide CNV data in 603 Danish nonagenarians and centenarians (mean age 96.9 years, range 90.0–102.5 years). Replication was performed in 500 long‐lived individuals from the Leiden Longevity Study (mean age 93.2 years, range 88.9–103.4 years). First, we assessed the association between the CNV burden of each individual (the number of CNVs, the average CNV length, and the total CNV length) and mortality and found a significant increase in mortality per 10 kb increase in the average CNV length, both for all CNVs (hazard ratio (HR) = 1.024, P = 0.002) and for duplications (HR = 1.011, P = 0.005), as well as per 100 kb increase in the total length of deletions (HR = 1.009, P = 0.0005). Next, we assessed the relation between specific deletions and duplications and mortality. Although no genome–wide significant associations were discovered, we identified six deletions and one duplication that showed consistent association with mortality in both or either of the sexes across both study populations. These results indicate that the genome–wide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long‐lived individuals.

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Section: Introductionmentioning

confidence: 99%

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

et al. 2015

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“…These results suggest a conserved role of attenuated LEPR expression in supporting of human ALL development. LEPR sensitivity can be affected by LEPR gene polymorphism 42,43 , which would not be detected in microarray experiments. To further study the role of LEPR signaling in human leukemia, we expanded the survival analysis to all known LEPR-signaling-related genes 44 .…”

Section: Rps6ka2mentioning

confidence: 99%

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

Xie

et al. 2016

Nat Med

116

114

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Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types [1][2][3][4][5][6] . Fasting can promote hematopoietic stem cell-based regeneration and reverse immunosuppression [7][8][9] , and has been reported to promote the anti-cancer effects of chemotherapy 5,10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown.AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults [11][12][13] . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. RESULTSFasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14-22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25,26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation (Fig. 1a) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice (Fig. 1b,c). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks posttransplantation (Fig. 1c,d).Next, we measured the distribution of B lymphoblastic cells and myeloid cells in the GFP + compartment of the B-ALL mice. Control mice with B-ALL had 65-80% of B220 + cells (pan B lineage marker) and 0.5-2% of Mac-1 + cells (myeloid lineage marker) in GFP + fractions of PB, BM and SP (Fig. 1e,f), indicative of fully developed B-ALL. By contrast, there were only 19-28% of B220 + cells and 5-12% of Mac-1 + in GFP + fractions in fasted mice (Fig. 1e,f), consistent with loss of the B-ALL phenotype. There was also a higher percentage of New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered ...

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“…(e) The differentiated neurons displayed key functional properties of hypothalamic neurons, including the ability to accurately process and secrete neuropeptides (αMSH, BEP, AGRP) and to respond to metabolic signals such as insulin and leptin. GWAS and whole-exome sequencing studies continue to identify many candidate genes for human obesity (47)(48)(49). The functional analysis of these candidates in rodents is time consuming, costly, and subject to strain-related effects on phenotypes related to energy homeostasis and diabetes (50)(51)(52).…”

Section: Differentiation Of Hypothalamic Arc-like Neurons From Ipscsmentioning

confidence: 99%

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Wang¹,

Meece²,

Williams³

et al. 2015

J. Clin. Invest.

116

125

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Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity

Cited by 287 publications

References 26 publications

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

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