New kids on the block : the functions of obesity genes identified by GWAS - John Speakman
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New kids on the block : the functions of obesity genes identified by GWAS John Speakman Institute of Genetics and Developmental biology Chinese Academy of Sciences Beijing, China
Twin and family studies suggest that 65% of the variation in body fatness is genetic But these studies don’t tell us which genes are involved Genome Wide Association Studies (GWAS) are an attempt to find these genes
GWAS studies link polymorphic variation (SNPs) in the
genome to a phenotype of interest
LOD score
Manhatten plot
Position along chromosome
Note: GWAS identifies SNPs
not genes
GWAS : Body mass index 5 studies with >50,000 subjects So far identified about 40 SNPs linked to BMI Largest study c 250,000 subjects (Speliotes et al 2010 Nature Genetics 42: 937-948)
BUT
BMI is not a very good
phenotype to characterise
Body fatness
Romero-Corral et al (2008)
Int. J. Obesity 32: 959-966
GWAS based on CT scan estimates of fatness
Fox et al (2012)
Plos Genetics
8:e102695
Confirms only 8 of
these SNPs
(n = 10557)
SNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
SNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
rs9816226 Intronic ETV5 ETS variant gene 5 ETS family member All ETS family members share 85 AA DNA binding domain Act as transcription factors ETV5 has strong known links to several cancers Highly expressed in the Hypothalamus Expression is related to nutritional status Mechanism of action unknown
SNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
rs 9969309 intronic FTO
Original name Fused TOes from deletion mutation in mice
First gene linked to obesity by GWAS
(Frayling et al 2007 Science 316: 889-894)
Renamed FaT mass and Obesity associated
Largest effect size of all GWAS genes (gene dose 1.5 kg/at risk alelle)
FTO protein is an oxoglutarate
dependent DNA/RNA demethylase
(Gerken et al 2007 Science 318: 1469-
1472)
Expressed in brain (plus many other
tissues)CONFUSING effects – mice and humans
HUMANS
In humans the ‘at risk’ A- alelle is associated with > FOOD
INTAKE (500-1250 kJ/day) but it is NOT linked to energy
expenditure
(Speakman et al 2008: Obesity 16: 1961-1965)
Since verified in at least 10 independent studies
MICE
In mice KO of the FTO gene appears to affect body composition via effects
on energy EXPENDITURE not food intake
Fischer et al (2009) Nature 458 894-898
Since verified in 2 other studies
(also lots of other effects on growth)Potential resolution (??)
Although gene variants are intronic in FTO their main effect may be on
expression of next gene along IRX-3 (Smemo et al 2014: Nature eprint)
Intronic FTO snp is more closely
linked to gene expression of
IRX-3 than FTO
IRX-3 FTOIRX-3 KO mice are leaner and protected from HFD induced obesity IRX-3 is a transcription factor in the brain
IRX-3 KO mouse (Smemo et al 2014)
IRX-3 KO mouse –
obese phenotype
?Effects on food intake
/expenditure unclear
Emphasizes that even though SNP is intronic, its effect may be in a different geneSNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
rs2815752 IG NEGR1 Neuronal growth regulator 1
Widely found in the brain – particularly hippocampus
Function not exactly clear : Neurite outgrowth
cell-cell adhesion
synaptogenesis
SNP is linked to food intake in humans
Gene expression co-localises with 2 populations of neurons
in the hypothalamus
1) Arginine-vasopressin/oxytocin neurons (in supraoptic
nucleus and paraventricular nucleus)
2) Neurons in the Ventromedial nucleus and Arcuate
nucleus (responsive to feeding state)NEGR-1 From Speakman (2013) Human heredity 75: 57-79
NEGR1 KO mouse has a body weight phenotype (KO is lighter) Lee et al 2012 Plos One 7: e41537 BUT this is entirely due to differences in lean tissue mass NOT fat mass Contrasts situation in humans where SNP effect is on fat mass (CT study)
Impact on energy expenditure – due entirely to lower lean mass in the KO
More recently suggested to have functions outside the brain 1) It is linked to adipogenesis. Expression of gene 2x up during adipogenesis. siRNA knockdown inhibits adipogenesis (Bernhard et al 2013 Diabetologia 56: 311-322.) 1) Gene is at the hub of an expression network in adipose tissue (Walley et al 2012 International journal of obesity 36: 137-147)
Total picture may include both central and peripheral effects From Speakman (2013) Human heredity 75: 57-79
SNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
rs2867125 IG TMEM18 Trans-membrane protein 18
Transmembrane protein
Located predominantly on nuclear
membrane
3 trans-membrane domains
Long N and C terminal ends
C-terminus binds DNA
From Almen et al (2010) BMC medical genomics
Dimerisation increases specificity of bindingRAT MOUSE Highly expressed in the brain – but levels unresponsive to nutritional status Expressed in many other tissues – may have peripheral and central functions
From Speakman (2013) Human heredity 75: 57-79
SNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1
Exonic - SNP leads to alanine to therionine substitution
at AA 484 of 767 AA protein
Known component of leptin signalling pathwayLeptin-JAK-STAT pathway
(adapted from Morris and Rui
2009 AJP 297: E1247-1259)
SH2B1
SH2B1
Enhances activity of JAK2
Enhances recruitment of
STAT to JAK
Enhances leptin signal
Promoting satietySH2B1 KO mouse is highly susceptible to obesity (Ren et al 2005 Cell metabolism 2: 95-104) Mouse has 60% greater food intake (plus greater energy expenditure) SH2B1 also has peripheral impacts on insulin signalling and glucose homeostasis
SNP Location Nearest gene rs9939609 Intronic FTO FaT mass and Obesity associated rs2815752 IG NEGR1 Neuronal growth regulator 1 rs2867125 IG TMEM18 Trans-membrane protein 18 rs9816226 Intronic ETV5 ETS variant gene 5 rs2112347 IG POC5/FLJ35779 Centrosomal protein rs10968576 Intronic LINGO rs7498665 Exonic SH2B1 Src-homology 2B adaptor protein 1 rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor
rs2287019 Intronic GIPR Gastric inhibitory polypeptide receptor GIP – 1970 40AA peptide from duodenum gastric inhibitory polypeptide Now recognised as an incretin hormone stimulating insulin release (Glucose-dependent insulinotrophic polypeptide) Large receptor population in the pancreas mediating incretin effect Receptors also on adipose tissue and in the brain. In these locations appears related to body weight control Direct infusion of GIP in humans stimulates appetite and reduces energy expenditure (Daousi et al 2009 Clinical endocrinology 71: 195-201)
In mice knocking out the GIPR globally leads to a protection from high fat Diet induced obesity
Global KO added back to adipocytes added back to beta cells Adding back expression of GIPR to either adipoctes or beta cells removes the protection effect of the global KO Mechanisms unknown..
From Speakman (2013) Human heredity 75: 57-79
Summary 1. There is much that we don’t understand about how the main genes identified by GWAS affect obesity 2. The nearest gene to a GWAS SNP may not necessarily be the affected gene (cf FTO versus INX-3) 3. Effects of the genes in mice may be different from the effects in humans 4. Although they are almost all expressed in the brain they may also have significant peripheral expression and functions
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