250 II. BIOLOGICAL  FOuNDATIONS
In 2016, a published meta-  analysis of 
GWA results of 106,716 individuals, of 
which 91,370 are part of the large U.K. Bio -
bank project, identified nine novel loci for 
neuroticism (Smith et al., 2016). Two of the 
loci were in very large linkage disequilibrium 
(LD) blocks containing many genes, which 
makes it difficult to link these loci to any 
specific gene. Other loci represented smaller 
regions containing a single gene. Some inter -
esting candidate genes were found, many of 
which are expressed in the brain and have 
some known neuronal function, including 
GRIK3,  which is a glutamate receptor gene 
(for the full list of genes associated with the 
index SNPs, see Table 10.1). The MAGI1  
gene as identified by de Moor et al. (2015) 
was not confirmed in this study, although 
the direction of effect was the same. At 
about the same time as the study from Smith 
et al. (2016), Okbay et al. (2016) published a 
study in which the U.K. Biobank results for 
neuroticism were meta-  analyzed together 
with the Genetics of Personality Consortium 
(GPC) results for harmonized neuroticism.5 
This study reported 11 loci for neuroticism, 
of which five can be considered novel loci, 
since they were not found in either of the 
studies from De Moor et al. (2015) or Smith 
et al. (2016), or previous GWA studies. Of 
note is the genomewide significant finding 
on chromosome 11q, near the dopamine 
receptor D2 ( DRD2 ) gene. DRD2  was also 
found to be significantly associated in some 
candidate gene studies reviewed in Munafò 
et al. (2003), but after correcting for hetero -
geneity in findings, the association became 
nonsignificant. It should be noted, however, 
that the polymorphism studied was not the 
same in the genomewide versus the candidate 
gene studies. In general, candidate genes are 
rarely detected in GWA studies, and with 
the exception of DRD2,  this also appears to 
be the case for studies on personality.
In 2017, another meta-  analysis of ge -
nomewide studies for the five FFM person -
ality traits was published (Lo et al., 2017). 
In this meta-  analysis, data from 23andMe 
were combined with data from the GPC for 
agreeableness, openness to experience, and 
conscientiousness, harmonized neuroticism, 
and harmonized extraversion. For neuroti -
cism, two loci were found, of which one was 
also identified in the studies from Smith et al. (2016) and Okbay et al. (2016): a large 
LD block on chromosome 8p23.1, which 
contains many genes. As suggested by both 
Okbay et al. (2016) and Lo et al., (2017) this 
region might contain multiple independent 
associations that might be accounted for by 
an inversion polymorphism in this region. 
Lo et al. (2017) also combined the results 
of 23andMe, GPC, and the U.K. Biobank 
in one large meta-  analysis of 260,861 sub -
jects, and showed that this locus was highly 
significant with a p value of 3.17 × 10–24 
and 3.95% of the variance in neuroticism 
explained, which is the largest effect size 
found in a GWA study for personality that 
is attributable to a single SNP. The other 
loci found for neuroticism, extraversion, 
and conscientiousness have all been found in 
other GWA studies for related phenotypes, 
including psychiatric phenotypes and educa -
tional attainment (Lo et al., 2017).
The most recent GWA meta-  analysis, 
studying just neuroticism, included data 
from the U.K. Biobank, 23andMe, and the 
GPC, reaching a sample size of 449,484 sub -
jects (Nagel et al., 2018). This study reports 
136 genomewide significant loci (of which 
124 were new at the time of analysis) that 
could be linked to many genes involved in 
specific brain cell types, including dopami -
nergic neuroblasts, medium spiny neurons, 
and serotonergic neurons. Gene set analyses 
suggest pathways involved in neurogenesis, 
behavioral response to cocaine processes, 
and axon part.
Overall, these large meta-  analytic stud -
ies show that if sample sizes in GWA stud -
ies are sufficiently large (i.e., hundreds of 
thousands), genetic variants can be detected 
at genomewide significant levels, that is, be -
yond levels of chance, taking into account 
the multiple association tests performed in 
a genomewide study. It further shows that 
the likelihood of replication of findings is 
also increased across cohorts if sample sizes 
are very large, as evidenced by the detection 
of the 18p23.1 locus for neuroticism. The 
effect sizes are, however, very small, and 
much of the genetic variance as estimated 
in heritability studies remains unexplained. 
SNP-based heritability studies give more in -
sight in what causes this discrepancy, also 
known as “the missing heritability problem” 
(Maher, 2008).