Identification of a pathogenic<i>FTO</i>mutation by next-generation sequencing in a newborn with growth retardation and developmental delay

Daoud, Hussein; Zhang, Dong; McMurray, Fiona; Yu, Andrea C.; Luco, Stephanie M.; Vanstone, Jason; Jarinova, Olga; Carson, Nancy; Wickens, James; Shishodia, Shifali; Choi, Ho-Jin; McDonough, M.A.; Schofield, Christopher J.; Harper, Mary‐Ellen; Dyment, David A.; Armour, Christine M.

doi:10.1136/jmedgenet-2015-103399

Cited by 56 publications

(44 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, these mice also display a considerable reduction in lean mass. Moreover, late-onset systemic deletion of Fto in the adult mouse also resulted in increased total fat mass and decreased lean mass (45), and individuals lacking FTO display growth retardation (30,31). In our study, congenital systemic Ftonull mice displayed reduced lean mass and elevated adiposity by 20 weeks of age (data not shown).…”

Section: Lepr-bmentioning

confidence: 75%

“…The reduction of hypothalamic FTO in fasted mice (18,19), and the in vivo findings presented above indicating that P200 overproduction decreased hypothalamic Fto expression and was associated with decreased energy expenditure and increased food intake, prompted us to test the hypothesis that Fto hypomorphism per se increases adiposity. We measured the body composition of mice systemically deleted for exon 3 of one Fto wild-type allele (Fto +/-) (29), as loss of both Fto copies results in severe loss of lean mass in mice and humans (29)(30)(31). Fto +/-male mice fed standard chow until the age of 14 weeks were approximately 16% heavier than control (+/+) mice ( Figure 3A; P < 0.05).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

Stratigopoulos¹,

Burnett²,

Rausch³

et al. 2016

Journal of Clinical Investigation

100

View full text Add to dashboard Cite

Section: Lepr-bmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

Stratigopoulos¹,

Burnett²,

Rausch³

et al. 2016

Journal of Clinical Investigation

100

View full text Add to dashboard Cite

“…To illustrate the application of the relationship described in Equation (13) to experimental data, we used GWAS data around the well-established obesity locus, FTO , generated by a recent large study of extreme BMI (Berndt et al, 2013). The FTO gene encodes for an alpha-ketoglutarate-dependent dioxygenase (Gerken et al, 2007), playing a role in growth and development (Boissel et al, 2009; Daoud et al, 2016), and has been reliably associated with the related conditions of type 2 diabetes, BMI, adiposity and other obesity-related traits (Scott et al, 2007; Zeggini et al, 2007; Lindgren et al, 2009; Thorleifsson et al, 2009; Fox et al, 2012; DIAGRAM Consortium et al, 2014; Wood et al, 2016). Within the FTO gene region, the study found that rs11075990 exhibited the strongest association with extreme BMI with a reported p -value of 9.3E-33.…”

Section: Resultsmentioning

confidence: 99%

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem

et al. 2016

View full text Add to dashboard Cite

Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. Specifically, the ratio of Chi-square disease association statistics at a marker site and causal site is equivalent to the standard measure of pairwise linkage disequilibrium, r2. A complete derivation of this relationship from a general disease model is shown. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non-interrogated causal site using data at closely linked markers. Lastly, we apply this way of examining association data from high-density genotyping in a large, publicly-available data set investigating extreme BMI. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods and provide new avenues for identifying causal sites/genes from fine-mapping studies.

show abstract

“…To illustrate the application of the relationship described in Equation (13) to experimental data, we used GWAS data around the wellestablished obesity locus, FTO, generated by a recent large study of extreme BMI (Berndt et al, 2013). The FTO gene encodes for an alpha-ketoglutarate-dependent dioxygenase (Gerken et al, 2007), playing a role in growth and development (Boissel et al, 2009;Daoud et al, 2016), and has been reliably associated with the related conditions of type 2 diabetes, BMI, adiposity and other obesity-related traits (Scott et al, 2007;Zeggini et al, 2007;Lindgren et al, 2009;Thorleifsson et al, 2009;DIAGRAM Consortium et al, 2014;Wood et al, 2016). Within the FTO gene region, the study found that rs11075990 exhibited the strongest association with extreme BMI with a reported p-value of 9.3E-33.…”

Section: Application To Experimental Datamentioning

confidence: 99%

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem

Maadooliat

Bansal

Upadhya

et al. 2016

Preprint

View full text Add to dashboard Cite

Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. A complete derivation of this relationship from a general disease model is shown for very large sample sizes. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non-interrogated causal site using data at closely linked markers. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods.

show abstract

Identification of a pathogenicFTOmutation by next-generation sequencing in a newborn with growth retardation and developmental delay

Cited by 56 publications

References 29 publications

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem

Contact Info

Product

Resources

About