 10. Molecular Genetics of Personality  245
identifying the genomic regions that might 
harbor genes for personality. With sample 
sizes of around 200–1,300 sib pairs, these 
studies have probably been underpowered. 
Furthermore, it has proven to be quite dif -
ficult to locate regions with enough preci -
sion (Roberts, MacLean, Neale, Eaves, & 
Kendler, 1999). Nowadays, genomewide 
linkage studies are not considered to be the 
most suitable technique to identify genes for 
complex traits (i.e., phenotypes that are in -
fluenced by many common genetic variants 
with each small effect size) (McCarthy et al., 
2008; Stranger, Stahl, & Raj, 2011). Mo -
lecular genetics researchers have now turned 
to genomewide association studies as a more 
promising approach to find genetic loci for 
personality traits. Genomewide association 
(GWA) studies resemble genomewide link -
age studies in that a genomewide “search” 
is conducted, without an a priori hypothesis 
about which genetic loci are likely to be as -
sociated with personality. However, GWA 
studies are quite different from genomewide 
linkage studies in the sense that they are not 
conducted in families tracing the cosegrega -
tion of genetic variants and traits. Rather, 
they are conducted in samples of unrelated 
individuals and rely on standard regression 
techniques in which the association between 
a genetic variant and a phenotype is tested.3 
This technique is also the basis of candidate 
gene association studies, in which a specific 
genetic variant, mostly located in or near a 
well-  characterized candidate gene, is tested 
for association with the phenotype based on 
a theory-  driven a priori hypothesis.4 In the 
next section, I first discuss such candidate 
gene association studies for personality. This 
is followed by a section reviewing GWA 
studies for personality.
Candidate Gene Association  Studies
In 1996, two years before the first genome -
wide linkage study for personality appeared, 
the first candidate gene association studies 
for personality were published, one study fo -
cusing on a serotonin gene and neuroticism/
harm avoidance traits (Lesch et al., 1996) 
and two other studies focusing on a dopa -
mine gene in relation to novelty seeking/
disinhibition (Benjamin et al., 1996; Ebstein 
et al., 1996). The first study examined the association between a VNTR ( 5-HTTLPR ) 
in a promoter region near the serotonin 
transporter gene ( 5-HTT  or SLC6A4 ) on 
chromosome 17 and anxiety-  related person -
ality traits, among which were neuroticism 
and harm avoidance (Lesch et al., 1996), 
testing the hypothesis that anxiety-  related 
personality traits are correlated with geneti -
cally influenced serotonergic brain function -
ing. In a sample of 505 individuals, higher 
neuroticism was associated with one or two 
copies of the short allele of 5-HTTLPR . 
In addition, 5-HTTLPR  was also signifi -
cantly associated with measures of anxiety 
and harm avoidance. Ever since, the study 
has been cited over 5,000 times, and many 
studies have attempted to replicate the origi -
nal findings. Subsequently, the results of 
these studies have been summarized by sev -
eral meta-  analyses (Munafò, Freimer, et al., 
2009; Schinka, Busch, & Robichaux-  Keene, 
2004; Sen, Burmeister, & Ghosh, 2004). In 
the meta-  analysis by Sen et al., which includ -
ed 23 studies on 5-HTTLPR  and anxiety- 
related personality traits in adults, it was 
found that 5-HTTLPR  was significantly 
associated with neuroticism ( p = .000016), 
but not with harm avoidance ( p = .166) or 
other anxiety-  related personality traits ( p 
= .944). Schinka et al. (2004) arrived at a 
similar conclusion, meta-  analyzing 26 stud -
ies showing that the effect size for the as -
sociation between 5-HTTLPR  and anxiety- 
related personality overall was very small ( d 
= 0.10), but larger for neuroticism ( d = 0.23) 
compared with harm avoidance ( d = 0.04). 
These two meta-  analyses were followed by 
a third meta-  analysis in 2009, including 42 
studies, that confirmed that 5-HTTLPR  
is not significantly associated with harm 
avoidance ( d = 0.02, p = .37) or Eysenck -
ian neuroticism ( d = 0.01, p = .71), but there 
is evidence for association with FFM-based 
neuroticism ( d = 0.18, p < .001) (Munafò, 
Freimer, et al., 2009). These outcomes lend 
only partial support for Cloninger’s hypoth -
esis that serotonergic brain activity is in -
volved in anxiety-  related personality traits. 
Munafò, Freimer, et al., in their discussion 
of the meta-  analysis results, question the 
usefulness of finding a genetic effect that is 
specific to an FFM measure of neuroticism 
(the NEO Personality Inventory—  Revised 
[NEO-PI-R]).