Download Synthe'c associa'on and the ‘missing heritability problem’  Carl Anderson  Sta's'cal Gene'cs   

Synthe'c associa'on and the ‘missing heritability problem’ Carl Anderson Sta's'cal Gene'cs [email protected] SEGEG ‐ UCL Wednesday 1st December 2010 The ‘missing heritability problem’ Maher, Nature 456, 18‐21 (2008) Finding the missing heritability of complex diseases Manolio et al, Nature, Vol 461, October 2009 SEGEG ‐ UCL Wednesday 1st December 2010 Quan'fying the ‘missing heritability problem’ Trait Number of known loci Heritability explained Age‐related macular degenera'on 7 >50% Crohn’s disease 71 23% Height 180 20% BMI 32 6‐11% Type‐2 diabetes 37 10% Schizophrenia 1‐2 <1% SEGEG ‐ UCL Wednesday 1st December 2010 Resolving the ‘missing heritability problem’ 1) More loci to be uncovered a) common SNPs of weak effect (polygenic model) b) low frequency SNPs (whole‐exome/genome sequencing) c) other types of varia'on (CNVs, indels etc) 2)  More variance at each locus a) mul'ple causal effects at each locus b) more complex models (i.e non addi've variance – GxG, GxE) c) less heritability d) synthe'c associa'on (Dickson et al, PLoS Biol. 2010 Jan 26;8(1):e1000294) SEGEG ‐ UCL Wednesday 1st December 2010 What is synthe'c associa'on? NOD2 example )#$
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Orozco et al, Hum Mol Genet, 2010 SEGEG ‐ UCL Wednesday 1st December 2010 NOD2 and Crohn’s disease: A synthe'c associa'on Best common NOD2 tag SNP: 0.8% Three rare coding muta'ons: ~5% Anderson et al, PLoS Biol, in press. SEGEG ‐ UCL Wednesday 1st December 2010 Synthe'c associa'on and the ‘missing heritability problem’ “We show that they are not only possible, but inevitable, and that under simple but reasonable gene'c models, they are likely to account for or contribute to many of the recently iden'fied signals reported in genome‐wide associa'on studies.” “efforts to iden'fy causal variants responsible for GWAS signals that concentrate on a region of high LD surrounding the implicated variant are not well mo'vated and are likely to miss many and perhaps most of any rare variants that contribute to synthe'c associa'ons” SEGEG ‐ UCL Wednesday 1st December 2010 Synthe'c associa'on does not underlie most GWAS signals The Evidence 1.
The gene'c model underlying synthe'c associa'on is very tractable via linkage analysis, but linkage was almost completely unsuccessful in mapping complex disease genes. SEGEG ‐ UCL Wednesday 1st December 2010 Power to detect synthe'c associa'on SEGEG ‐ UCL Wednesday 1st December 2010 Power to detect synthe'c associa'on: Linkage vs. Associa'on Model: RAF = 1% α = 1x10‐4 3 causal loci 5 causal loci 9 causal loci SEGEG ‐ UCL Linkage: 2,657 ASPs (T1DGC) Concannon et al (2009) Associa'on: 2,000/2000 cases/controls Wednesday 1st December 2010 If synthe'c associa'on is common, should be many overlaps between loci iden'fied in linkage and GWAS studies Taken from T1Dbase (hsp://t1dbase.org/) SEGEG ‐ UCL Wednesday 1st December 2010 Power to detect synthe'c associa'on: Linkage vs. Associa'on MHC INS CTLA4 SEGEG ‐ UCL Wednesday 1st December 2010 Power to detect synthe'c associa'on: Linkage vs. Associa'on Back to NOD2 SEGEG ‐ UCL Wednesday 1st December 2010 Synthe'c associa'on does not underlie most GWAS signals The Evidence 1.  The gene'c model underlying synthe'c associa'on is very tractable via linkage analysis, but linkage was almost completely unsuccessful in mapping complex disease genes. 2.  Resequencing around GWAS hits has, so far at least, produced lisle support for synthe'c associa'on. SEGEG ‐ UCL Wednesday 1st December 2010 Resequencing has not iden'fied synthe'c associa'ons However, it is clear that rare and common varia'on both underlie complex diseases Inspired Metabo/immunochip 1.5% 0.67% 0.93% 2.2% 39% SEGEG ‐ UCL Wednesday 1st December 2010 Synthe'c associa'on does not underlie most GWAS signals The Evidence 1.  The gene'c model underlying synthe'c associa'on is very tractable via linkage analysis, but linkage was almost completely unsuccessful in mapping complex disease genes. 2.  Resequencing around GWAS hits has, so far at least, produced lisle support for synthe'c associa'on. 3.  Pathway analyses refute the no'on that causal variants are rou'nely very distant from GWAS hit SNPs (i.e. beyond recombina'on hotspots) SEGEG ‐ UCL Wednesday 1st December 2010 Where do you think the causal gene for sickle cell diseases is? SEGEG ‐ UCL Wednesday 1st December 2010 Th17 signalling pathway in Crohn’s disease Distance from GWAS hit SNP to gene: •  IL23R – 0kb •  STAT3 – 0kb •  JAK2 – 3kb •  TYK2 – 0kb Non‐random pathway overlap: P < 0.001 SEGEG ‐ UCL Wednesday 1st December 2010 Synthe'c associa'on does not underlie most GWAS signals The Evidence 1.  The gene'c model underlying synthe'c associa'on is very tractable via linkage analysis, but linkage was almost completely unsuccessful in mapping complex disease genes. 2.  Resequencing around GWAS hits has, so far at least, produced lisle support for synthe'c associa'on. 3.  Pathway analyses refute the no'on that causal variants are rou'nely very distant from GWAS hit SNPs (i.e. beyond recombina'on hotspots). 4.  GWAS hit SNPs are oten associated in samples of different con'nental ancestries. SEGEG ‐ UCL Wednesday 1st December 2010 GWAS signals frequently consistent across different ancestry groups Tan et al. JCEM. 95:390‐397 (2010). SEGEG ‐ UCL Wednesday 1st December 2010 But not at NOD2… Gasche et al., 2008. SEGEG ‐ UCL Wednesday 1st December 2010 Summary •  The preponderance of evidence suggests that complex human diseases are influenced by common, low frequency and rare muta'ons, and a hypothesis invoking mul'ple rare variants is compa'ble with the common disease common variant hypothesis. •  Linkage, local resequencing, pathway analysis and transcon'nental replica'on all suggest that synthe'c associa'ons, though they do exist, are not responsible for most GWAS signals. Therefore, unlikely to explain much of the current “missing heritability”. •  Common SNP associa'ons arising from GWAS studies are just that: common SNP associa'ons. •  Sequencing studies focussing on regions around GWAS loci are well founded. •  Large scale whole‐exome and whole‐genome sequencing studies are undoubtedly the next step. Very much needed to get at low‐frequency and rare variants but we shouldn’t sully the legacy of GWAS in the process. SEGEG ‐ UCL Wednesday 1st December 2010 Acknowledgements Jeff Barres Nicole Soranzo Ele Zeggini UK IBD Gene'cs Consor'um Anderson et al. Synthe:c associa:ons are unlikely to account for many common disease genome‐wide associa:on signals. PLoS Biol. In Press. Issue will also included another commentary by Naomi Wray, Shaun Purcell and Peter Visscher, a response to both ar'cles by David Goldstein and an editorial. SEGEG ‐ UCL Wednesday 1st December 2010