246 II. BIOLOGICAL  FOuNDATIONS
Two other early candidate gene studies 
on personality appeared back-to-back in the 
same issue of Nature Genetics  in 1996, and 
both examined the association between the 
dopamine receptor D4 ( DRD4 ) gene and 
novelty seeking (Benjamin et al., 1996; Eb -
stein et al., 1996). In the study from Ebstein 
et al., the most common long allele (7-repeat) 
of the DRD4  exon III polymorphism was 
found to be associated with higher scores 
on novelty seeking in sample of 124 adults. 
Benjamin et al. (1996) replicated these find -
ings by showing in sample of 315 subjects, 
that the DRD4  exon III long alleles (6–8 
repeats) were associated with higher scores 
on extraversion and with lower scores on 
conscientiousness compared to short alleles 
(2–5 repeats). In addition, the DRD4  exon 
III polymorphism was significantly associat -
ed with estimated scores on novelty seeking. 
Many studies have aimed to replicate these 
findings since then, with very mixed results, 
Munafò et al. (2003), in a meta-  analysis that 
included studies examining the association 
between candidate genes in the serotonin 
and dopamine neurotransmitter pathways 
(including but not restricted to 5-HTT  and 
DRD4 ), concluded that only the association 
between 5-HTTLPR  and avoidance traits 
such as neuroticism and harm avoidance re -
mained significant ( p = .038).
Given the difficulties in replicating the 
original findings of associations between 
serotonin-  related and dopamine-  related 
genes and personality traits, as illustrated 
by Munafò et al. (2003), researchers have 
further moved into broadly two directions 
in the search for genetic variants for person -
ality. Some researchers have argued that the 
genetic effects may be confounded by ex -
posures to environments, and state that we 
can only detect genetic effects if we consider 
their interaction with the environment (Bel -
sky & Pluess, 2009; Caspi, Hariri, Holmes, 
Uher, & Moffitt, 2010). However, similar 
problems arise in these gene × environment 
(G × E) interaction studies in that the origi -
nal G × E effects are often difficult to repli -
cate, as has been shown for example for the 
interaction effect between 5-HTTLPR  and 
stressful life events on depression (Munafò, 
Durrant, Lewis, & Flint, 2009; Risch et al., 
2009), which was also found to be absent 
for neuroticism (Middeldorp et al., 2010). Other researchers have argued that follow -
ing the successes of GWA studies for medi -
cal phenotypes, we should conduct similar 
studies for social, behavioral, and psychiat -
ric phenotypes in order to identify novel loci 
that enable the generation of novel hypoth -
eses about the underlying (neuro)biological 
mechanisms of these phenotypes (Cichon et 
al., 2009). Once such genetic variants are 
robustly identified, the possibility of study -
ing the moderating effect of the environment 
can be considered. I discuss such GWA stud -
ies in the next section.
Genomewide Association  Studies
GWA studies have become feasible since the 
entire human genome was mapped in 2003 
(Altshuler et al., 2005) and some technical 
advances occurred in our ability to geno -
type tens of thousands of SNPs (Barrett & 
Cardon, 2006). In such studies, hundreds 
of thousands or even millions of SNPs, cov -
ering a large part of the common genetic 
variation along the genome, are tested for 
association with a particular phenotype 
(Hirschhorn & Daly, 2005). The first GWA 
studies for personality were published in 
2008, just five years after the completion 
of the human genome map. Lessons had 
been learned from the abundance of non -
replications found in both candidate gene 
association and genomewide linkage stud -
ies. Therefore, these initial GWA studies 
already comprised samples of considerably 
larger size (thousands rather than hundreds 
of subjects), frequently included a replica -
tion sample, and used stringent significance 
thresholds to deal with the multiple tests 
performed in GWA studies and the associat -
ed risk of false-  positive discoveries. In GWA 
studies, hundreds of thousands or millions 
of genetic variants are typically tested, and 
associations with p values below 5 × 10–8 are 
considered significant genomewide.
The first two GWA studies focused on 
neuroticism (Shifman et al., 2008; van den 
Oord et al., 2008). In the study by Shifman 
et al. (2008), no genomewide significant hits 
were found in a sample of around 2,000 
individuals, but one variant in the PDE4D  
gene on chromosome 5 was suggestively as -
sociated with neuroticism ( p < .001) that 
was marginally associated ( p < .05) with 