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.

A whole genome association study of neuroticism using DNA pooling

“…The sample Individuals were selected from the patient registers of general practices in four counties in southwest England, that is, Oxfordshire, Gloucestershire, Somerset and Berkshire (as described by Fullerton et al 14 and Martin et al 27 ). We chose patients in rural practices, so that the sample is likely to be relatively genetically homogeneous.…”

“…The first population, originally selected for neuroticism linkage mapping, consists of one member of extremely concordant and discordant sibling pairs (as described by Fullerton et al 14 and Martin et al 27 ), while the second population, collected for genetic association, consists of singletons (as described by Willis-Owen et al 24 ). For the singletons, we received around 20% replies to our request of DNA samples.…”

“…[6][7][8][9] The correlation between anxiety, major depression and neuroticism is, in part, due to the presence of shared genetic factors, [10][11][12][13] an observation that has spurred attempts to map the genetic basis of neuroticism. [14][15][16] It is much easier to acquire the large samples necessary for genetic studies of neuroticism, which is assessed using a self-administered questionnaire, than it is to acquire large patient samples that require diagnostic interviews for accurate assessment of major depression and anxiety.…”

“…One study of extremely discordant and concordant siblings identified five loci that exceeded a 5% genomewide significance threshold, 14 but a second study, also using a selected sample, failed to identify any genome-wide significant signals. 15 One explanation for the difficulties encountered is that the proportion of genetic variance attributable to an individual locus is extremely small, so that the linkage studies are underpowered.…”

COMT Polymorphisms and Anxiety-Related Personality Traits

“…Moreover, particularly in the case of major depression, there is evidence that neuroticism interacts with psychosocial stress to yield psychopathology (Kendler et al, 2003(Kendler et al, , 2004. As such, elucidating the genetics of personality traits such as neuroticism may contribute to a better understanding of the etiology of these disorders (Bienvenu and Stein, 2003;Fullerton et al, 2003;Reif and Lesch, 2003;Van Gestel and Van Broeckhoven, 2003). …”