 10. Molecular Genetics of Personality  247
neuroticism in one out of the four replica -
tion samples. In a sample of 1,227 subjects, 
Van den Oord et al. (2008) found sugges -
tive evidence that neuroticism was associ -
ated with the MAMDC1  gene (also labeled 
the MDGA2  gene). This locus could be rep -
licated using a nominal p -value threshold 
of .05 in a sample of 1,880 Germans. The 
MAMDC1  locus could also be replicated in 
a study on harm avoidance in 541 healthy 
individuals and 199 depressed patients 
(Heck et al., 2011) but not for neuroticism 
in another study (Hettema, van den Oord, 
An, Kendler, & Chen, 2009).
Terracciano et al. (2010) published the 
first GWA study on the five FFM personal -
ity traits in a sample of 3,972 subjects from 
a genetically isolated population. Again, no 
genomewide significant signals were found, 
but some interesting and suggestively signif -
icant associations were reported: between 
neuroticism and SNAP25,  extraversion and 
BDNF  and two cadherin genes, and agree -
ableness and the CLOCK  gene, a gene in -
volved in circadian rhythms. The association 
between CLOCK  and agreeableness could 
be replicated in two out of three samples; 
the other associations were not replicated. In 
the same year, a GWA study ( N = 5,117) on 
the four Cloninger temperament traits was 
published (Verweij et al., 2010). Again, no 
genomewide significant hits were found.
These early GWA studies seemed to con -
firm that personality traits are indeed highly 
polygenic and suggested that even larger 
sample sizes with more statistical power are 
required to detect genetic variants that ac -
count for the heritability of personality. At 
that time, it became clear to molecular genet -
ics researchers interested in complex pheno -
types such as personality traits that in order 
to increase sample size, data from multiple 
cohorts needed to be pulled together and 
analyzed by meta-  analytic techniques. An 
overview of the meta-  analytic genomewide 
association studies for personality pub -
lished since then is provided in Table 10.1. 
de Moor et al. (2012) conducted the first 
meta-  analysis of GWA studies for personal -
ity, focusing on the five FFM dimensions of 
personality assessed in 10 different samples, 
with a total sample size of 17,375 individu -
als. Replication of top signals was sought 
in five independent samples comprising an additional 3,294 subjects. Together, these 
cohorts formed the start of the Genetics of 
Personality Consortium, a large collabo -
ration between cohorts with data on both 
genomewide genotypes and personality. 
Genomewide significant loci were found for 
openness to experience near the RASA1  gene 
on chromosome 5 and for conscientiousness 
in the brain-  expressed KATNAL2  gene on 
chromosome 18, although these associations 
were not clearly replicated. Surprisingly, no 
genomewide significant loci were detected for 
neuroticism, the personality trait on which 
most molecular genetics studies focused in 
the past. Around the time that this paper ap -
peared, meta-  analyses of GWA studies for 
other complex traits, such as height, showed 
that if sample size is further increased, the 
technique is able to detect much more genetic 
variants (see, e.g., the successes for the mo -
lecular genetics study of height, for which 
180 loci were identified in over 180,000 indi -
viduals; Allen et al., 2010). In order to maxi -
mize sample size beyond the ~17,000 indi -
viduals included in the study from de Moor 
et al. (2012), a harmonization procedure was 
developed that linked the personality ques -
tionnaires from Eysenck’s, Cloninger’s, and 
FFM models of personality. The procedure 
resulted in harmonized estimated scores for 
neuroticism/harm avoidance and extraver -
sion/reward dependence in over 63,000 indi -
viduals from 29 cohorts (van den Berg et al., 
2014). A meta-  analysis was conducted on the 
GWA results for the harmonized neuroticism 
and extraversion in these cohorts (de Moor 
et al., 2015; van den Berg et al., 2016). For 
neuroticism, a replication cohort of almost 
10,000 individuals was also available. A ge -
nomewide significant association was found 
for neuroticism with a variant in the MAGI1  
gene on chromosome 3. This variant was not 
significant genomewide in the replication co -
hort, but remained significant genomewide 
in the meta-  analysis of all 30 cohorts. The 
MAGI1  gene is expressed in the brain, par -
ticularly in the hippocampus, and has been 
linked to major depression, schizophrenia, 
and bipolar disorder—  disorders that are 
known to be genetically correlated to each 
other and with neuroticism. For extraver -
sion, no genomewide significant hits were 
found in the same cohorts and the equally 
large sample size (van den Berg et al., 2016).