252 II. BIOLOGICAL  FOuNDATIONS
ity traits from GPC (de Moor et al., 2012), 
uniquely predicted diagnoses of major de -
pressive disorder (MDD) and bipolar disor -
der (BD) in independent samples. Polygenic 
risk scores for neuroticism predicted MDD, 
while polygenic risk scores for extraversion 
predicted BD. The prediction of MDD from 
polygenic scores for neuroticism was con -
firmed by de Moor et al. (2015). Okbay et 
al. (2016) estimated the genetic correlations 
of neuroticism with depressive symptoms, 
subjective well-being, and a range of neuro -
psychiatric and physical health phenotypes, 
by investigating the overlap of the GWA re -
sults of all these phenotypes. Neuroticism 
was genetically correlated to both depres -
sive symptoms ( rg = .70) and subjective well-
being ( rg = –.75). The genetic correlation of 
neuroticism with anxiety disorders was also 
large; smaller yet significant genetic correla -
tions were found with BD and schizophre -
nia. Neuroticism was not found to be ge -
netically correlated with Alzheimer’s disease 
or autism spectrum disorder. With regard 
to physical health phenotypes, neuroticism 
was not found to be genetically correlated 
with body mass index, fasting glucose or 
triglycerides, but small genetic correlations 
were found with coronary heart disease and 
ever smoking (Okbay et al., 2016). Lo et al. 
(2017), using the same technique as Okbay 
et al. (2016), computed the genetic correla -
tions among the Big Five personality traits 
and six psychiatric disorders: MDD, BD, 
schizophrenia, attention-  deficit/hyperactiv -
ity disorder (ADHD), autism spectrum dis -
order, and anorexia nervosa. Neuroticism 
was highly genetically correlated with MDD 
(rg = .56); extraversion showed a moderate 
genetic correlation with ADHD ( rg = .30). 
Openness to experience was moderately cor -
related with schizophrenia, BD, and MDD 
(rg from .28 to .36). MDD was further genet -
ically correlated with not only neuroticism 
and openness to experience but also agree -
ableness and conscientiousness (moderate 
negative correlations). Principal component 
analysis of the genetic correlation matrix 
further showed that the five personality 
traits and six psychiatric phenotypes can 
be grouped along two genetic dimensions: 
the first dimension mainly separating per -
sonality traits from psychiatric phenotypes, 
and the second dimension reflecting an externalizing–  internalizing distinction (Lo 
et al., 2017). Nagel et al. (2018) also report 
a range of significant genetic correlations 
between neuroticism and subjective well-
being (–.68) and between neuroticism and 
a range of psychiatric phenotypes (.20–.82, 
with 0.79 for MDD). Taken together, these 
studies show clear genetic overlap among 
personality traits on the one hand and psy -
chiatric phenotypes on the other. Moreover, 
neuroticism is most prominently genetically 
linked to internalizing disorders such as 
MDD and anxiety disorders, whereas ex -
traversion is linked to ADHD and BD. In 
a previous section of this chapter, I showed 
that GWA studies have begun to robustly 
identify specific loci for personality, such as 
the 18p locus for neuroticism. An important 
next step would be to further characterize 
the function of such loci in human (brain) 
tissues, and to relate this functional knowl -
edge to insights into the genetic and neurobi -
ological etiology of psychiatric phenotypes.
Conclusion and  Future  Directions
Over the past few decades, important prog -
ress has been made in the search for genetic 
variants associated with personality traits 
that might explain the well-  established 
heritability of personality. A shift has taken 
place from relatively small studies that either 
search the entire genome for loci but are not 
so powerful and precise (linkage studies) or 
studies that focus on just a few candidate 
genes (candidate gene association studies) 
toward much larger, more powerful studies 
that cover a large portion of the genetic vari -
ation on the human genome (GWA studies). 
New techniques have been developed in the 
context of GWA studies, such as meta- and 
mega-  analysis, and techniques that use ge -
nomewide SNP data to estimate SNP-based 
heritability for single traits and compute 
genetic correlations among multiple traits: 
personality traits, and psychiatric and other 
related phenotypes. These techniques have 
been successfully applied to the molecular 
genetics study of personality, and show that 
personality traits are highly polygenic and 
genetically overlap with other mental and 
behavioral phenotypes. The efforts of large-
scale GWA studies that identify single vari -