Genome-wide linkage analysis of multiple measures of neuroticism of 2 large cohorts from

Australia and the Netherlands.

Wray, N. R. et al. (2008). Archives of General Psychiatry, 65(6), 649-658.

Motivation

• Disorders of anxiety and depression are phenotypically and genotypically correlated with N– Understanding normal variation in N may help

understand these disorders• nb: traits are of interest in their own right too!

Paucity of significant linkages

Participants

• Nineteen thousand six hundred thirty- five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years.

• 5069 sib-pairs genotyped with microsatellite markers.

Power

• 89% power to detect suggestive linkage of a QTL accounting for 10% of the phenotypic variance.

• QIMR sample, for instance, has <30% power to detect a significant effect accounting for 10% of the ∂2

• h2 of N is perhaps as low as 30%– 2*sib-correlation = 2*.15 = .3

Sidebar: Power

• http://pngu.mgh.harvard.edu/~purcell/gpc/

• http://www.sph.umich.edu/csg/abecasis/CaTS/

Methods

• Nonparametric linkage analyses were con-ducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time.– Regresses estimated IBD (identity by descent)

between relative pairs on the squared sums and squared differences of trait values of the pairs.

• Consistency examined by comparing general results to time- and sample-specific linkages

Subjects

• Australian Twin Registry twins of North European ancestry

• Questionnaires• 23-item EPQ-R)• 12-item subset (EPQ-RS)• 12-item NEO FFI-R• EDAC design used to ascertain 1999 (EPQ-R)

sample

ExtremeDiscordantAndConcordant

• Gains of 10-40 fold in sample size by selecting pairs of sibs who are either:

Extremely discordantOr

Both concordant, and extreme on the trait

• Risch, N. and Zhang, H. (1995). Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science, 268, 1584-1589

Extreme Groups

Measures• Australian Twin Registry twins of North European ancestry• Questionnaires

– 23-item EPQ-R)– 12-item subset (EPQ-RS)– 12-item NEO FFI-R

• EDAC design used to ascertain 1999 (EPQ-R) sample

• Netherlands– Amsterdamse Biografische Vragenlijst

• Yes, No, don't know

Sample

Results

Results

Tutorial SidebarLander, E. and Kruglyak, L. (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics, 11, 241-247.

With an infinitely dense linkage mapP<.05 around 2 dozen times by chance (once on each chromosome).P<.01 still 7-8 timesP<.001 more than onceP<.0001 about .2 timesP<.00002 about .05 times

We’d like results that would occur less than .05 times per analysis by chance so:genomewide-significance P < .2*10-5, Z ≥ 4.1, lod ≥ 3.6“suggestive” = once by chance per genome = lod ≥ 2.2 “replication” =p.05 in an interval = .01 at a point = lod ≥ 1.1

Linkage results

Discussion points

• Tons of room for a Nobel prize in personality.• What really is the heritability of Personality?• 19%?– Pilia, G., et al. (2006). Heritability of cardiovascular and

personality traits in 6,148 Sardinians. PLoS Genet, 2, doi.• Is ‘N’ an endophenotype?– Do measures of N confound different traits?

• How large are the QTLs?– Nothing over 10% (or perhaps 1%)?

Shifman, S., … Flint, J. (2008). A whole genome association study of neuroticism using DNA pooling.

Mol Psychi, 13, 302-12.• We describe a multistage approach to identify single nucleotide polymorphisms (SNPs)

associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)>2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.

Discussion points

• Tons of room for a Nobel prize in personality, and no competition as yet.

• What really is the heritability of Personality?• 19%?

– Pilia, G., et al. (2006). Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet, 2, doi.

• How large are the QTLs?– Nothing over 10% (or perhaps 1%)?

• Is ‘N’ an endo phenotype?• Do measures of N mix traits?