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.