Missing Heritablility How to Analyze Your Own Genome Fall 2013

Transcription

1 Missing Heritablility How to Analyze Your Own Genome Fall 2013

2 Heritability Heritability: the propor>on of observed varia>on in a par>cular trait (as height) that can be agributed to inherited gene>c factors in contrast to environmental ones

3 Heritability Heritability can be es>mated from the regression of offspring phenotypic values on the average of parental phenotypic values

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5 Missing Heritability Height is 80-90% heritable Using a single SNP analysis In GWAS over 30,000 people, more than 40 loci were found to be associated with the height Only 5% of the height s heritability is explained by the gene>c varia>on at those 40 loci Analyzing all SNPs jointly for their influence on height 45% of the height s heritability is explained by SNPs How can we explain the missing heritability?

6 Missing Heritability Studies looking at similari>es between iden>cal and fraternal twins es>mate heritability at more than 90% for au>sm and more than 80% for schizophrenia O[en, the gene>c loci found by GWAS explain a small frac>on of the heritability

7 Explaining Missing Heritability Undetected epistasis Going beyond SNPs Structural variants: inser>ons, dele>ons, duplica>on, copy number variants Heritability es>mate could be wrong. Environment (e.g., diet) can be heritable within families Epigene>cs changes in gene expression that are inherited but not caused by changes in gene>c sequence Feeding a mouse a certain diet, for example, can alter the coat color not only in its children, but also in its children s children. Here, the expression of a coat- color gene is controlled by a type of DNA modifica>on (epigene>c modifica>on) called methyla>on. From common variants to rare variants

8 Common Variants vs. Rare Variants First- genera>on genome- wide associa>on study (GWAS): common variant common disease hypothesis Common low- penetrance variants (Penetrance: the likelihood that the causal loci will in fact have an effect on the phenotype) Common variants with minor allele frequency (MAF)>5% dbgap: ~11 million SNPs HapMap: 3.5 million SNPs A successful GWAS requires a more complete catalogue of gene>c varia>ons Rare variants (MAF<0.5%), low- frequency variants (MAF:0.5%~5%) Captured by sequencing with next- genera>on sequencing technology Rare, moderately penetrant alleles Possibly significant contributors to the gene>c architecture of disease Causal variants are subject to nega>ve selec>on

9 1000 Genome Project (The 1000 Genome Project ConsorBum, Nature 2010) The goal is to characterize over 95% of variants that are in genomic regions accessible to current high- throughput sequencing technologies and that have allele frequency of 1% or higher (the classical defini>on of polymorphism) in each of five major populabon groups (popula>ons in or with ancestry from Europe, East Asia, South Asia, West Africa and the Americas) individuals (low coverage) - 6 individuals in two trios (deep sequencing) individuals (exon sequencing of 8,140 exons)

10 1000 Genome Projects: Known vs. Novel Variants

11 AssociaBons to Rare Variants O[en GWA studies are underpowered for func>onal rare variants Common Variant Associa>on Case Control Allele a Allele A Rare Variant Associa>on Case Control Allele a 7 2 Allele A Common variant GWA approaches are appropriate only for common variants

12 Recent Methods for DetecBng Rare Variant AssociaBons Test combined effect of mul>ple rare variants Fixed- Threshold Approach (Li & Leal, AJHG 2008) Include only the SNPs with allele frequency below a fixed threshold For SNP i=1,,m in a genomic region or a gene, Score = m ε i i=1 C» : The allele frequency of SNP i in cases C i i» ε = 1 i 0 If the allele frequency of SNP i is below a specified threshold Otherwise Evaluate the significance of Score

13 Feasibility of IdenBfying Disease Loci

14 Summary Missing heritability: GWAS had only limited success 1000 Genome Project for obtaining a more complete catalogue of gene>c varia>ons in human genomes Post GWAS Rare variants Epigene>c varia>on Structural varia>on