Genetic contributions to complex traits in a post genomewide era Nic Timpson ALSPAC – The first 21 years conference 2012

ALSPAC – The first 21 years conference 2012

** ** * * Nature of genetic analyses/phenotype gene mapping GENOME Candidate gene studies Our best candidates examined specifically in population based samples. Genomewide linkage studies Physical events in the genome (recombination) tracked through families with monitored patterns of segregation with phenotype. Genomewide association studies Within populations, patterns of correlation between common variants (1-5%) are exploited to assess the 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

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: 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 2006/7 ALSPAC – The first 21 years conference 2012

Example: Definition of FTO effect Science 2007;316: ALSPAC – The first 21 years conference 2012

GIANT_3 (n~250,000) ALSPAC – The first 21 years conference 2012

BUT, are these genes for obesity? ?? FTO effect ~0.1SD across the distribution

ALSPAC – The first 21 years conference 2012

IndividualPlatform Read Length Base coverage Genomic coverage Cost ($US) J. Craig Venter Automated Sanger N/A70,000,000 James D. WatsonRoche/ ,000,000 Yoruban male Illumina/ Solexa ,000 Yoruban male Life/APG ,000 Nat Rev Genet Jan;11: ALSPAC – The first 21 years conference 2012

Data (bytes) ~20Tb Based on n~5000 ~$5 + billion ~$70 million ~$1 million ~$ Per genome HGP Venter & Watson NGS 1- Candidate 2- CHIP (designer) 3- Affy Intensity data 5- NGS data (*LC) ~10Gb ~2Mb Consequent shifting budgets… ALSPAC – The first 21 years conference 2012

Word map of high-throughput sequencers

ALSPAC – The first 21 years conference 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 across both 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.