Behavioral Genetics and Polygenic Risk Scores
From Twin Studies to GWAS
Polygenic Architecture of Traits
Genome-Wide Association Studies (GWAS) have revealed that most psychological traits, such as intelligence or risk for schizophrenia, are highly polygenic—influenced by thousands of genetic variants with minuscule individual effects. A Polygenic Risk Score (PRS) aggregates this risk for an individual : where is the number of SNPs, is the effect size of SNP , and is the allele count (0, 1, or 2).
Heritability Estimates
| Method | Concept | Typical Estimate (e.g., Schizophrenia) |
|---|---|---|
| Twin Studies | Proportion of variance explained by all genetic factors (narrow-sense heritability, ) | ~80% |
| SNP Heritability () | Proportion of variance explained by genotyped SNPs only | ~20-30% |
The Missing Heritability Problem
The gap between twin heritability and SNP heritability is known as 'missing heritability'. It is largely attributed to rare variants not captured by standard genotyping arrays, structural variants, and incomplete Linkage Disequilibrium (LD) between genotyped SNPs and true causal variants.
Calculating a Polygenic Risk Score (PRS)
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1
Obtain GWAS summary statistics from a large discovery sample.
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2
Perform Quality Control (QC) on the target sample's genotype data.
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3
Clumping and Thresholding: Remove SNPs in high Linkage Disequilibrium (LD) and filter by a p-value threshold.
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4
Score calculation: Sum the risk alleles in the target sample, weighted by their discovery effect sizes.
What is a primary reason that SNP heritability estimates are generally lower than twin study heritability estimates?
Genotyping arrays only capture a fraction of genetic variation. If causal variants are not in perfect Linkage Disequilibrium with the measured SNPs, their full effect won't be captured, leading to lower heritability estimates.
Correct answer: Incomplete Linkage Disequilibrium (LD) between genotyped SNPs and causal variants.
What statistical phenomenon describes the non-random association of alleles at different loci, causing them to be inherited together more often than expected by chance?
Linkage Disequilibrium (LD) is a fundamental concept in genetics where alleles that are physically close on a chromosome tend to be inherited together.
Correct answer: Linkage Disequilibrium