Genetic contributions to complex traits in a post genomewide era
Nic Timpson
ALSPAC – The first 21 years conference 2012
2000 2007
ALSPAC – The first 21 years conference 2012
ALSPAC – The first 21 years conference 2012
* * * * * *
Nature of genetic analyses/phenotype gene mapping
GENOMECandidate gene studies
Our best candidates examined specifically in population based samples.
Genomewide linkage studies
Physical events in the genome (recombination) tracked throughfamilies with monitored patterns of segregation with phenotype.
Genomewide association studies
Within populations, patterns of correlation between common variants (1-5%) are exploited to assessthe relationship between a representation of all genomic variation at this frequency and phenotype.
Whole genome sequencing studies
Within populations, ALL genotypic variation is assessed by massively parallel local sequence capture.This provides a measure of all types of variation at all frequencies across the population for analysis against phenotypic variation.
ALSPAC – The first 21 years conference 2012
ALSPAC – The first 21 years conference 2012
“We anticipate that our data, results and software, which will be widely available to other investigators, will provide a
powerful resource for human genetics research.”
TCF7L2
FTO
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-678.
A natural extension to the dissection of this anomalous GWAS hit…
Generate a specific phenotypic analysis within the detailed ALSPAC resource.
Notes from WTCHG Dec/Jan 2006/7ALSPAC – The first 21 years conference 2012
Example: Definition of FTO effect
Science 2007;316:889-894.
ALSPAC – The first 21 years conference 2012
GIANT_3 (n~250,000)
ALSPAC – The first 21 years conference 2012
ALSPAC – The first 21 years conference 2012
BUT, are these “genes for obesity”?
??
FTO effect ~0.1SDacross the distribution
ALSPAC – The first 21 years conference 2012
Individual Platform Read
LengthBase
coverageGenomic coverage
Cost ($US)
J. Craig Venter Automate
d Sanger 800 7.5 N/A 70,000,000
James D. Watson Roche/454 250 7.4 95 1,000,000
Yoruban male Illumina/
Solexa 35 40.6 99.9 250,000
Yoruban male Life/APG 50 17.9 98.6 60,000
Nat Rev Genet. 2010 Jan;11:31-46.
ALSPAC – The first 21 years conference 2012
1 2 3 4 52000000
20000000
200000000
2000000000
20000000000
200000000000
2000000000000
20000000000000
1 2 3 4 559999.9999999999
599999.999999999
5999999.99999999
59999999.9999999
600000000
6000000000
60000000000
600000000000
6000000000000
Data
(byte
s)
~20Tb
Based on n~5000
~$5 + billion
~$70 million
~$1 million~$ 60 000
Per genome
HGP Venter & Watson
NGS
1- Candidate2- CHIP (designer)3- Affy 5004- Intensity data5- NGS data (*LC)
~10Gb
~2Mb
Consequent shifting budgets…
ALSPAC – The first 21 years conference 2012
ALSPAC – The first 21 years conference 2012
http://omicsmaps.com/
Word map of high-throughput sequencers
ALSPAC – The first 21 years conference 2012
50 high-priority phenotypes
2. Imputation of rare variants
GWAS
6,000 TwinsUK
9,000 (+)
ALSPAC
3. Direct association with QTs
UK10K disease sets
4. Population-based controls
1. Whole-genome sequence (6x)
2,000 TwinsUK
2,000 ALSPAC
Cohorts component of UK10K
ALSPAC – The first 21 years conference 2012
Complex phenotype genetics in ALSPAC, the next 21 years…
Nature news feature April 2012
Key targets:
(i) Processing, cleaning and analysis of new genetic data collections.
(ii) Consolidation of existing resources acrossboth ALSPAC young participants and mothers including the maximisation of genotypic data across ALL samples.
(iii) New data opportunities – fathers and next generation(iv) Integration of data from many sources – coordinated examination of “multi-omic” data which is available often longitudinally across the entire collection.
Measurement “snapshots” of complex life histories.
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