Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism

Abstract

Several theoretical studies have suggested that large samples of randomly ascertained siblings can be used to ascertain phenotypically extreme individuals and thereby increase power to detect genetic linkage in complex traits. Here, we report a genetic linkage scan using extremely discordant and concordant sibling pairs, selected from 34,580 sibling pairs in the southwest of England who completed a personality questionnaire. We performed a genomewide scan for quantitative-trait loci (QTLs) that influence variation in the personality trait of neuroticism, or emotional stability, and we established genomewide empirical significance thresholds by simulation. The maximum pointwise P values, expressed as the negative logarithm (base 10), were found on 1q (3.95), 4q (3.84), 7p (3.90), 12q (4.74), and 13q (3.81). These five loci met or exceeded the 5% genomewide significance threshold of 3.8 (negative logarithm of the P value). QTLs on chromosomes 1, 12, and 13 are likely to be female specific. One locus, on chromosome 1, is syntenic with that reported from QTL mapping of rodent emotionality, an animal model of neuroticism, suggesting that some animal and human QTLs influencing emotional stability may be homologous.

Figure  1

Scatterplots of the distribution of neuroticism scores for each sibling pair. The scale is a standardized residual of the transformed sex- and age-regressed neuroticism scores. A, Distribution of entire sample. B, Distribution of selected sample.

Figure  2

Multipoint linkage analysis of the genome for individual variation in neuroticism. The −logP values (vertical axis) for the Visscher-Hopper regression are shown (Visscher and Hopper 2001). The cumulative distance is given at the bottom, and chromosome numbers are given at the top. The two dotted, horizontal lines represent the empirically derived genomewide significance thresholds (5% and 1%).

Figure  3

The −logP values (vertical axis) of a t test for deviation from the expected mean IBD across the autosomal chromosomes. Distance is given at the bottom.

Figure  4

Genomewide linkage analysis for individual variation in neuroticism in female-female (red line) and male-male (black line) sibling pairs. The −logP values (vertical axis) for the Visscher-Hopper regression are shown (Visscher and Hopper 2001). The cumulative distance is displayed at the bottom, and chromosome numbers are given at the top.