5-ht1a gene variants and psychiatric disorders: a review of current

5-HT1A gene variants and psychiatric disorders :a review of current literature and selectionof SNPs for future studies

Antonio Drago, Diana De Ronchi and Alessandro Serretti

Institute of Psychiatry, University of Bologna, Italy

Abstract

5-HT1A receptors are key components of the serotonin system, acting both pre- and post- synaptically

in different brain areas. There is a growing amount of evidence showing the importance of 5-HT1A in

different psychiatric disorders, from mood to anxiety disorders, moving through suicidal behaviour and

psychotic disorders. Findings in the literature are not consistent with any definite 5-HT1A influence in

psychiatric disorders. 5-HT1A gene variants have been reported to play some role in mood disorders,

anxiety disorders and psychotic disorders. Again, the literature findings are not unequivocal. Concerning

response to treatment, the C(-1019)G variant seems to be of primary interest in antidepressant response:

C allele carriers generally show a better response to treatment, especially in Caucasian samples. Together

with the C(-1019)G (rs6295) variant, the Ile28Val (rs1799921), Arg219Leu (rs1800044) and Gly22Ser

(rs1799920) variants have been investigated in possible associations with psychiatric disorders, also with

no definitive results. This lack of consistency can be also due to an incomplete gene investigation. To make

progress on this point, a list of validated single nucleotide polymorphisms (SNPs) covering the whole

gene is proposed for further investigations.

Received 2 July 2007; Reviewed 20 September 2007; Revised 27 September 2007; Accepted 7 October 2007;

First published online 30 November 2007

Key words : Depression, mood disorders, psychiatric genetics, serotonin, serotonin receptor 1A.

Introduction

Why this receptor is important: evidence

Serotonin (5-hydroxytryptamine or 5-HT) is an in-

trinsically fluorescent biogenic amine, which acts

as a neurotransmitter by binding to a class of trans-

membrane receptors termed serotonin receptors

(Chattopadhyay et al., 1996). These receptors rep-

resent one of the largest, evolutionarily ancient, and

highly conserved families of G-protein-coupled re-

ceptors (GPCR) (Peroutka and Howell, 1994). Through

specific receptors, 5-HT mediates a large variety of

cognitive and behavioural functions including sleep,

mood, pain, addiction, locomotion, sexual activity,

depression, anxiety, alcohol abuse, aggression, and

learning (Artigas et al., 1996; Ramboz et al., 1998) ;

since all those functions are receptor-mediated, gen-

etic variations of the receptor coding sequences are of

primary interest for psychiatric research.

There is a number of known mammalian 5-HT re-

ceptor genes (5-HT1A/B/D/E/F, 5-HT2A/B/C, 5-HT3A/B

and 5-HT3C/D/E, 5-HT4, 5-HT5A/B, 5-HT6, 5-HT7) some

of which encode additional receptor variants (Albert

and Lemonde, 2004) ; within this group, 5-HT1A is

one of the most investigated; more than 1750 research

papers up to January 2007 are dedicated to this pro-

tein.

5-HT1A is a G protein-associated receptor, pre-

ferentially coupled to Gi/o proteins to inhibit adenylyl

cyclase. Many other second-messenger cascades have

been associated with 5-HTR1A activation: MAPK

pathways (which may be excitatory in post-synaptic

cells or inhibitory in presynaptic neurons), c-Jun

N-terminal kinase, GH/IGF-1 receptors and NMDA

receptor channels (Adayev et al., 2003; Appert-Collin

et al., 2005; Chen et al., 2002; Cowen et al., 1996, 2005;

Millan et al., 2001; Stark et al., 2007; Sullivan et al.,

2005; Turner et al., 2007; Yuen et al., 2005). Influence

on inwardly rectified potassium channels (Andrade

and Nicoll, 1987; Grunnet et al., 2004) and endo-

crine hormones secretion (Serres et al., 2000) have also

been reported. Interestingly, membrane proved to

play a relevant functional role : Evans and colleagues

Address for correspondence: A. Serretti, M.D., Institute of Psychiatry,

University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy.

Tel. : +39 051 6584233 Fax : +39 051 521030

E-mail : [email protected]

International Journal of Neuropsychopharmacology (2008), 11, 701–721. Copyright f 2007 CINPdoi:10.1017/S1461145707008218

REVIEW ARTICLE

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showed that the responsiveness of the 5-HT1A receptor

can be enhanced or depressed as a consequence of

activation of phospholipid-coupled receptor systems

(Evans et al., 2001), and Pucadyil and colleagues

showed that 5-HT1A activation is cholesterol-

dependent since there is evidence of 5-HT1A agonists

and antagonists inhibitory effects aftermembrane chol-

esterol oxidation (Pucadyil et al., 2005). This under-

lines the importance of the membrane environment

where receptor activation takes place, and gives fur-

ther details about the intracellular signal cascade,

highlighting the high complexity of cellular mech-

anisms. On this topic see also Kalipatnapu and Chat-

topadhyay (2005), for a review about the membrane

solubilization of 5-HT1A receptors. The aim of this

study is to review the literature evidence about asso-

ciations of 5-HT1A genetic variations and some of the

most important psychiatric disorders, clinical presen-

tation and treatment responses, attempting to high-

light the prerogatives and opportunities of this line of

research. This will follow a short review of receptor

distribution in the brain and a 5-HT1A coding sequence

description.

Where in the neurons?, where in the brain?

Brain 5-HT1A receptors are located both pre- and post-

synaptically. Presynaptic 5-HT1A autoreceptors are

located in the somatodendritic neuronal region, at the

site of the serotonergic cell bodies in the dorsal and

medial raphe nuclei, and they mediate a feedback

inhibition of the 5-HT system, the so called ‘short

feedback loop’, regulating the release of 5-HT by

modulating neurotransmitter synthesis, terminal re-

lease and cell discharge rate (Sprouse and Aghajanian,

1988). In greater detail, the short negative feedback

loop involves GABAergic cells which are stimulated

by serotonergic neurons via HTR2A/C, and in turn

stimulates the 5-HT1A receptors on the surface of the

serotonergic neurons which first stimulated them,

closing the auto-inhibition cycle. That is the reason

why blockade of the 5-HT autoreceptor 1A (and also

1B) can enhance the increase of extracellular 5-HT

levels achieved after selective serotonin reuptake

inhibitor (SSRI) treatment (see Hjorth et al., 2000

for a review). Moreover, the presynaptic 5-HT1A

down-regulation is believed to be associated with

therapeutic effects of serotonergic antidepressant

treatments and related to its time delay before onset

(de Montigny et al., 1984). Further, it is suggested that

multiple 5-HT1A subtypes govern different aspects of

5-HT function in the dorsal raphe nucleus (Stamford

et al., 2000), and the 5-HT system flexibility is also

enriched by action of opiate receptors and neurokinins

(substance P and neurokinin B) stimulating 5-HT

neurons via glutamatergic influences (see Guiard

et al., 2005 and Liu et al., 2002 for interesting papers on

this topic).

Mutual influences between deep serotonergic nuclei

and upper brain systems is the biological basis for

the ‘long feedback loop’ which is mainly mediated by

post-synaptic 5-HT1A receptors and involves cortico-

limbic areas probably influencing the activity of

GABAergic and glutamatergic neurons (Davis et al.,

2002). In fact, post-synaptic 5-HT1A receptors are

found at high density in limbic regions and in the

frontal, medial prefrontal and enthorhinal cortices

(Grunschlag et al., 1997; Pazos et al., 1985; Schmitz

et al., 1998), and the hippocampal regions and medial

prefrontal cortex (mPFC) seem to be of primary in-

terest for 5-HT1A investigation. In fact, the long feed-

back loop has been proposed to be of primary interest

in the antidepressant effect of drug treatments through

the down-regulation of post-synaptic 5-HT1A recep-

tors (Artigas et al., 1996). Focusing on the limbic sys-

tem, there is evidence that CA1 and CA3 hippocampal

pyramidal cells are mainly inhibited by 5-HT1A acti-

vation (Andrade and Nicoll, 1987; Okuhara and Beck,

1994; Segal et al., 1989; Zgombick et al., 1989). Indeed,

a neuronal activation can also be achieved after

5-HT1A stimulation, via 5-HT1A-mediated inhibition of

putative inhibitory interneurons (Schmitz et al., 1995;

Segal, 1990). This is quite interesting in view of the

recent great interest in hippocampal functions as-

sociated with psychiatric disorders, especially for the

possible influence of 5-HT tone on hippocampal

neurogenesis associated with depressive episodes or

disorders. This is consistent with the animal study by

Miquel and colleagues (1994), where 5-HT1A was

found to be highly expressed in the cortex and hippo-

campus of adult rats (for a review see also Elder et al.,

2006). Indeed, there is evidence that long-term anti-

depressant treatment (SSRI, tricyclics, ECT), is as-

sociated with increased 5-HT1A-mediated inhibitory

tone on CA3 hippocampal pyramidal cells (Haddjeri

et al., 1998), this being more evident after short-term

lithium augmentation (Haddjeri et al., 2000). There are

also conflicting findings: Knobelman and colleagues

suggested that 5-HT1A plays a larger role in regulating

5-HT release in the striatum and possibly other brain

regions innervated by the dorsal raphe nucleus (e.g.

cortex) than in the hippocampus, suggesting a major

role for 5-HT1B in that region (Knobelman et al., 2001).

Accordingly, Parsons and colleagues described a more

significant disinhibition of 5-HT release in the frontal

cortex than in the ventral hippocampus in 5-HT1A

702 A. Drago et al.


knockout rats after exposure to SSRIs (Parsons et al.,

2001). Conflicting with this, a recent interesting report

showed 5-HT1A reduced density in the ventral hippo-

campus, which is primarily implicated in emotional

processing in the offspring of stressed female rats

(Van den Hove et al., 2006).

An important role in brain functioning, reasonably

related to psychiatric disorders, is played by the

mPFC: pyramidal neurons in the PFC integrate corti-

cal, thalamic, hypothalamic, limbic inputs and project

to many widespread neuronal structures. In turn, the

mPFC receives a large amount of afferences from the

same neuronal net. On this basis, the PFC regulates a

large number of cognitive and associative functions

and is involved in the planning and execution of

complex tasks, which are commonly impaired in some

of the most important psychiatric disorders such as

schizophrenia or severe depression. There is evidence

that 5-HT1A is highly expressed in the mPFC (Read

et al., 1994) and 5-HT1A is localized at an axon hillock

in the pyramidal neurons providing key negative

regulation of these neurons. Particularly in this area,

highly complex interactions with 5-HT2A and 5-HT1A

occur at the level of individual neurons (Amargos-

Bosch et al., 2004), thus leading to a difficult in-

terpretation of findings. For example, it has recently

been reported that higher 5-HT1A density in the PFC in

rats is associated with increased aggressive behaviour

(Caramaschi et al., 2007), probably through a dimin-

ished 5-HT tone. This conflicts with a previous ima-

ging study in humans which found that a lower

density of 5-HT1A was associated with a history of

aggressive behaviours in psychiatric patients and

healthy controls (Parsey et al., 2002). More research

efforts in this direction are needed.

Finally, 5-HT1A is expressed in other brain struc-

tures such as the cerebellar Purkinje cells (Darrow

et al., 1990), the midbrain periaqueductal grey (PAG, a

region known to be involved in pain modulation and

fear responses), the amygdala (a brain structure highly

associated with anxiety) (Behbehani et al., 1993; Davis

et al., 2002), sensory neurons of dorsal root ganglia

(Scroggs and Anderson, 1990), nucleus prepositus

hypoglossi (Bobker and Williams, 1990, 1995), ven-

tromedial hypothalamus (Newberry, 1992), lateral

septum (Joels et al., 1987; Van den Hooff and Galvan,

1992) and laterodorsal tegmental nucleus (Thakkar

et al., 1998) where 5-HT1A interaction was found to be

associated to modified REM sleep patterns.

With regard to brain layers, 5-HT1A can be found on

both pyramidal and principal cells, throughout the

neocortex (Azmitia et al., 1996; Miquel et al., 1994),

and it may have a role in the control of motor neuronal

excitability. Moreover, diminished serotonergic ac-

tivity might increase the release of neurotoxic levels of

glutamate, or play a direct neurotrophic role (Turner

et al., 2005). Finally, 5-HT1A can also be found

in calbindin- and parvalbumin-containing neurons,

which generally define two different subtypes of in-

terneurons (Aznar et al., 2003).

Those data taken together suggest a complex and

highly integrated 5-HT1A action in the brain: it is con-

ceivable that this receptor influences key regulation

activities in different parts of the brain reasonably

associated with psychiatric disorders. Even if the

physiological fine mechanisms of these actions are still

far from being understood, there is enough genetic

association evidence to encourage an effort towards

an evidence-based individual genetic approach with

diagnostic and therapeutic benefits.

The gene and its variants

The 5-HT1A receptor is encoded by an intronless

gene located on human chromosome 5q11.2–q13 and

it spans about 1200 bp (http://www.ncbi.nlm.nih.

gov/). It was first cloned by Fargin and Albert (Albert

et al., 1990; Fargin et al., 1989), and it encodes a single

receptor isoform, a protein 422 aa long. Fifty HTR1A

single nucleotide polymorphisms (SNPs) are known

so far, and 23 have been validated (http://snpper.

chip.org/bio/snpper-enter).

The most important linkage study results were

found for association between the long arm on chro-

mosome 5 and schizophrenia (Bassett, 1992; Crowe

and Vieland, 1998, 1999; Gorwood et al., 1991; Owen

et al., 1990), even though there are many conflicting

reports of linkage analysis (Chavarria-Siles et al., 2007;

Choudhury et al., 2007; Christoforou et al., 2007;

DeLisi et al., 2002; Jang et al., 2007; Le Hellard et al.,

2007; Liu et al., 2006; Ni et al., 2007; Schosser et al.,

2007), but many other reports can be found in the

literature.

Regarding bipolar disorder, there is some evidence

coming from linkage association studies for an in-

volvement of chromosome 5 (Kerner et al., 2007), even

though it should be considered that the dopamine

transporter gene is within 5p (Homer et al., 1997), and

in the distal 5q there are the genes for the glucocorti-

coid receptor (GRL) and the b2 adrenergic receptor

(ADRB2), also putatively involved in bipolar disorder

(Mirow et al., 1994). Conflicting with this, other link-

age association studies did not mention chromosome 5

(Barden et al., 2006; Faraone et al., 2006; Schumacher

et al., 2005; Underwood et al., 2006). There is also

evidence of linkage study exclusion of association

HTR1A and psychiatric disorders 703


between bipolar disorder and the whole chromosome

5 (Detera-Wadleigh et al., 1992), although using a less

dense marker coverage. No article reporting linkage

association analysis and supporting involvement of

chromosome 5 with unipolar depressive disorders, or

with suicidal behaviour, was found. Generally, even

though SNP association analysis give some interest-

ing results, linkage analysis studies investigating

chromosome 5 in association with psychiatric dis-

orders, showed almost negative results.

The most investigated HTR1A variants are:

C(-1019)G (rs6295); Ile28Val (rs1799921) ; Arg219Leu

(rs1800044) and Gly22Ser (rs1799920). C(-1019)G can

be found in the promoter zone of the gene and this

variant was found to be quite prevalent in the

normal population (Wu and Comings, 1999). Ile28Val

is characterized by a base-pair substitution (ApG) at

the first position of codon 28 in the putative amino-

terminal domain of the receptor (Bruss et al., 1995) ; the

Arg219Leu variant can be found in the third intra-

cellular loop of the 5-HT1A receptor (Bruss et al., 2005)

while the Gly22Ser variant is located in the putative

amino-terminal domain of the receptor (Rotondo

et al., 1997). C(-1019)G (rs6295) has a balanced allele

frequency in Caucasians, this makes investigations

useful since there is a good chance of finding patients

with all the allelic re6295 variants. On the other hand,

Arg219Leu (rs1800044) and Gly22Ser (rs1799920) have

no frequency data in the general population, and the

Ile28Val (rs1799921) G allele has a small prevalence in

Caucasians (0.8%). No prevalence data is available

for the other populations in international databases

(for all prevalence distribution, see Table 1). A small

probability of finding a carrier of a mutant allele

impairs the clinical impact of association studies based

on cited variations. This issue will be further dis-

cussed.

Expression and functions

Table 2 gives a list of expression studies in association

with 5-HT1A genetic variants. The main results and

significance are reported.

The 5-HT1A G(-1019) allele in the 5-HT1A upstream

regulatory region fails to bind identified repressors

Deaf-1 and Hes5, abolishing Deaf-1 action and im-

pairing Hes5 action. This leads to the up-regulation

of receptor expression (Albert and Lemonde, 2004;

Lemonde et al., 2003). In fact, an increase in 5-HT1A

receptor expression in individuals with the G/G

genotype has been observed (Parsey et al., 2006b).

Moreover, Deaf-1 has been shown to have a different

function in presynaptic and post-synaptic cells or

non-serotonergic neurons: it does not repress but

actually enhances the 5-HT1A expression in post-

synaptic cells (Czesak et al., 2006). This might help

explain some of the conflicting findings reported in the

literature : observations of cortical region-specific

decreases in the 5-HT1A receptor in PET studies of

psychiatric patients could be mediated by the disrup-

tion of Deaf-1 signalling leading to down-regulation of

5-HT1A expression in post-synaptic neurons. Another

interesting evidence and proposed explanation, is

highlighted by a PET study by David et al. (2005):

following the evidence of a decreased expression in

5-HT1A receptors in 5-HT transporter knock-out rats,

especially in females (Li et al., 2000), David and col-

leagues studied the mutual relationship between two

different gene variations: the 5-HT transporter and

5-HT1A. These authors reported that a minor avail-

ability of 5-HT1A was detected only in subjects (heal-

thy volunteers) with 5-HTTLPR short (SS or SL)

genotypes with no influence of 5-HT1A variants. A

possible explanation proposed was that the lower

transcriptional efficiency associated with the S allele

of 5-HTTLPR may lead to decreased 5-HTT function,

which in turn could lead to a lifelong increase in 5-HT

tone, which may then desensitize and down-regulate

5-HT1A receptors. This is consistent with animal

experiments : SERT knockout rats show a decreased

5-HT1A density (Li et al., 2004). Moreover, the absence

of increased 5-HT1A density in normal subjects with

the G/G genotype might also suggest that healthy

subjects can better compensate for their unfavourable

genetic make up than depressed patients.

Interestingly, in the same year Arias and colleagues

found that a combined genetic effect of HTR1A and

5-HTTLPR variants, and not the 5-HTTLPR variant

alone, could influence the antidepressant response in a

sample of 130 depressed patients, being the S/S G/G

the at risk haplotype for failed remission achievement

(Arias et al., 2005). It is really difficult to discuss the

partially different findings in these papers: the first

one, by David et al., is based on healthy subjects

and the second one, by Arias et al., investigates the

antidepressant (citalopram) response in a sample

of depressed subjects. Moreover, sample sizes are

different : 35 in the study by David and colleagues,

130 in the study by Arias et al. Stratification factors

such as different sociodemographic variables, co-

morbidity, pre-treatment issues such as response,

and type and duration of previous therapies in the

depressed sample make it difficult to draw definitive

conclusions.

Finally, a third hypothesis was proposed in 2002 by

Gross and colleagues (Gross et al., 2002) and in 2004 by

704 A. Drago et al.


Table 1. rs allele prevalence in different populations

rs Position Caucasian Asians (Han Chinese) Asians ( Japanese) Sub-Saharan African

rs6295

(C(-1019)G)aPromoter C=0.675 No frequency data No frequency data No frequency data

G=0.325

rs6295 Promoter C=0.675 No frequency data No frequency data No frequency data

G=0.325

rs10042486 Promoter C=0.517 C=0.133 C=0.125 C=0.271

T=0.483 T=0.867 T=0.875 T=0.729

rs6878612 Promoter A=0.510 A=0.087 A=0.090 A=0.250

G=0.490 G=0.912 G=0.910 G=0.750

rs7448024 Promoter A=0.942 A=1 A=1 A=1

C=0.058 C=0.0 C=0.0 C=0.0

rs6449694 Promoter No frequency data No frequency data No frequency data No frequency data


rs12653018 Promoter A=0.508 A=0.133 A=0.122 A=0.267

C=0.492 C=0.867 C=0.878 C=0.733


rs1799921

(Ile28Val)aExon A=0.992 No frequency data No frequency data No frequency data

G=0.008

rs1800044

(Arg219Leu)abExon No frequency data No frequency data No frequency data No frequency data

rs1799920

(Gly22Ser)abExon No frequency data No frequency data No frequency data No frequency data

rs6294 Exon A=0.0 G=1 A=0.211c A=0.065 No frequency data No frequency data

G=0.789c G=0.935

rs10085024 3k-UTR C=0.517 C=0.144 C=0.125 C=0.181

G=0.483 G=0.856 G=0.875 G=0.819

rs4521432 3k-UTR C=0.492 C=0.856 C=0.878 C=0.817

T=0.508 T=0.144 T=0.122 T=0.183

rs1364043 3k-UTR G=0.217 G=0.622 G=0.700 G=0.183

T=0.783 T=0.378 T=0.300 T=0.817

rs970453 3k-UTR No frequency data No frequency data No frequency data No frequency data

rs1423691 3k-UTR C=0.429 C=0.850c C=0.800 C=0.875 C=0.817

T=0.571 T=0.150c T=0.200 T=0.125 T=0.183



rs749099 3k-UTR A=0.490 A=0.830 A=0.770 No frequency

G=0.510 G=0.170 G=0.230 data


rs878567 3k-UTR C=0.483 C=0.867 C=0.878 C=0.742

T=0.517 T=0.133 T=0.122 T=0.258

rs6449693 3k-UTR A=0.483 A=0.867 A=0.878 A=0.742

G=0.517 G=0.133 G=0.122 G=0.258

rs10046068 3k-UTR C=0.99 C=0.99 C=0.99 C=0.842

T=0.01 T=0.01 T=0.01 T=0.158

rs13436914 3k-UTR C=0.01 C=0.078 C=0.056 C=0.347

T=0.99 T=0.922 T=0.944 T=0.653

rs13361335 3k-UTR G=0.050 G=0.622 G=0.700 G=0.133

T=0.950 T=0.378 T=0.300 T=0.867


aMost investigated; b not validated; c Afro Americans.



Lesch and colleagues (Lesch and Gutknecht, 2004) : the

influence of the 5-HT1A coding sequence variations

should not be expected to reveal itself through ex-

pression on adult neuronal surfaces, but by the com-

plex neuronal mutual net influences involved in brain

formation. Thus, the genetically determined 5-HT1A

enrichment would influence the neuronal net forma-

tion eventually predisposing to psychiatric disorders.

Evidence shows that 5-HT1A knockout rats show an

anxiety-like behaviour (Groenink et al., 2003; Heisler

et al., 1998; Olivier et al., 2001; Parks et al., 1998;

Parsons et al., 2001; Ramboz et al., 1998; Toth, 2003):

future animal research should be able to selectively

shut down pre- or post-synaptic 5-HT1A receptors, and

this would provide unique evidence for understand-

ing the detection of the predictive utility of genetic

variations.

The Arg219Leu variant was found to be expressed

in virtually identical densities in wild and variant

transfected HEK293 cells (Bruss et al., 2005), suggest-

ing that this variant has no influence over the stability

or efficiency of transductional and translational sys-

tems of the 5-HT1A coding sequence, even though it

was found that the ability of G-coupling activity after

receptor activation, and the inhibition of forskolin-

stimulated accumulation, was decreased by 60–90% in

variant type. In view of that, this variant apparently

does not change the binding properties of 5-HT1A, but

it is associated with a drastic impairment of signal

transduction: it seems reasonable to expect that

patients carrying the variant will show different drug

treatment responses.

A reduced receptor activity together with a lower

density on cell surfaces was also reported for the

Table 2. Expression studies

Study rs Sample Result Significance

Lemonde

et al. (2003)

C(-1019)G 129 Caucasian major depressed

patients

G associated with depression

and suicide

p=0.0017 (allele –

depression)

134 Caucasian controls 102

Caucasian suicide completers

p=0.002 (allele –

suicide attempters)

116 normal controls

Parsey et al.

(2006a)

C(-1019)G 43 controls Different genotype distribution

between non-remitters and

controls

p=0.005

22 depressed (medication-free) A trend in non-remitters to be

G carriers

p=0.0058

Parsey et al.

(2006b)

C(-1019)G 43 controls GG genotype associated with

depression

p=0.059

28 depressed (medication-free)

Czesak et al.

(2006)

C(-1019)G RN46A, septal SN48,

neuroblastoma SKN-SH,

neuroblastoma/glioma

NG108-15 cells

The intrinsic activity of Deaf-1

at the 5-HT1A promoter is

opposite in presynaptic vs.

post-synaptic neuronal cells

and requires deacetylation

pf0.01

Li et al.

(2000)

C(-1019)G serotonin (5-HT) transporter

knock-out mice (5-HTT x/x)

Reduced 5-HT1A density in

raphe, more extensively in

females

pf0.05

Bruss et al.

(2005)

Arg219Leu HEK293 cells The variant allele is associated

with impaired signal

transduction

pf0.05

Rotondo

et al. (1997)

Ile28Val

Gly22Ser

BamHI linearized eukaryotic

expression vector

Ser22 variant is capable of

attenuating agonist-mediated

receptor down-regulation and

desensitization

pf0.05

Erdmann

et al. (1995)

Ile28Val 352 patients 210 controls No different prevalence of

mutant allele

Not significant

Bruss et al.

(1995)

Ile28Val Cells No different pharmacological

profile between alleles

Not significant

706 A. Drago et al.


Gly22Ser variant but only after 24 h treatment with a

5-HT1A agonist, whereas the binding affinity and

pharmacological profile were found to be similar in

wild an variant genotype-expressing cells (Gothert

et al., 1998; Rotondo et al., 1997). In the same study

the Ile28Val variant was found not to influence affin-

ity, pharmacologically promoted or agonist-promoted

down-regulation issues. Most part of those investiga-

tions are over-expression studies in non-neuronal

cells : further validation in neuronal models or in vivo

would be advisable. Given that, a genetic approach

to patients will offer the opportunity to highlight a

different and predictable, i.e. genetically determined,

receptor drug treatment determined down-regulation,

which is the supposed therapeutic mechanism of anti-

depressant drugs. Finally, the Ile28Val variant was

found to be equally expressed in psychiatric and

healthy subjects (Erdmann et al., 1995), and to share

the same pharmacological profile with the wild vari-

ant (Bruss et al., 1995).

Table 3. Major depressive disorder


Parsey et al.

(2006a)

C(-1019)G 22 Caucasian depressed

(medication-free)

Different genotype distribution

between non-remitters and

controls

p=0.005

43 Caucasian controls A trend in non-remitters to be

G carriers

p=0.0058

Parsey et al.

(2006b)

C(-1019)G 28 Caucasian depressed

(medication-free)

GG genotype associated with

depression

p=0.059

43 Caucasian controls

Yu et al.

(2006)

C(-1019)G

Gly272Asp

222 Chinese major depressive

patients treated with 4-wk fluoxetine

G associated with worse

response in females

p=0.001

Hong et al.

(2006)

C-1019G 224 Chinese major depressive patients

treated with 4-wk fluoxetine


response to treatment

p=0.009

Arias et al.

(2005)

C-1019G 130 Caucasian major depressive

patients treated with citalopram


response to treatment when

associated with short HTTLPR

p=0.009

HTTLPR

Lemonde

et al. (2004)

C-1019G 118 Caucasian major depressive

patients treated with fluoxetine,

nefadozone, pindolol, flibanserin


response to treatment

p=0.0497

Lemonde

et al. (2003)

C(-1019)G 129 Caucasian major depressed

patients

G associated with depression

and suicide

p=0.0017 (allele –

depression)

134 Caucasian controls 102 Caucasian

suicide completers

p=0.002 (allele –

suicide

attempters)

116 normal controls

Mandelli

et al. (2006)

C(-1019)G 686 Caucasian depressive or bipolar

patients

No significant association Not significant

Peters et al.

(2004)

Various

SNPs

96 Caucasian major depressive patients

treated with 12-week fluoxetine


Serretti et al.

(2004)

C(-1019)G 151 Caucasian major depressed and

111 Caucasian bipolars treated with

6-wk fluoxetine


treatment response in bipolars

p=0.036

Kraus et al.

(2007)

C(-1019)G 139 hepatitis C-infected outpatients

treated with interferon ax2b

G associated with depression as

interferon treatment unwanted

side-effect

p=0.011

Levin et al.

(2007)

C(-1019)G 130 Caucasian major depressive

patients treated with SSRIs


Suzuki et al.

(2004)

Gly272Asp 65 Japanese depressed patients Gly associated with worse

treatment response

p=0.009

to p=0.031



Depression

Table 3 gives a list of studies dealing with major de-

pressive disorder (MDD) and antidepressant response

in association with 5-HT1A genetic variants. The main

results and significance are reported.

The 5-HT system is implicated in major depression

and suicide and is negatively regulated by somato-

dendritic 5-HT1A autoreceptors (Albert and Lemonde,

2004) ; moreover, desensitization of 5-HT1A auto-

receptors is believed to be related to the therapeutic

effects of antidepressant drugs and it is probably im-

plicated in the 2- to 3-wk latency for antidepressant

treatments (Blier et al., 1998). A significant decrease in

5-HT1A mRNA was found in the dorsolateral PFC and

hippocampus in chronically stressed animal models

and in subjects with MDD (Lopez et al., 1998; Lopez-

Figueroa et al., 2004).

This evidence makes the 5-HT1A genetic variants

good candidates in the pathophysiology and treat-

ment of depression. The G allele of the C(-1019)G

polymorphism has been reported to be associated with

enriched expression of the gene and there is some

evidence suggesting that G allele carriers have higher

risks for a depressive episode and of being more re-

sistant to antidepressant therapy (Arias et al., 2005;

Hong et al., 2006; Lemonde et al., 2003, 2004; Parsey

et al., 2006b; Yu et al., 2006), even though conflicting

evidence can also be found (Mandelli et al., 2006;

Peters et al., 2004; Serretti et al., 2004). On this topic,

our group reported some results in 2004: the sample

under investigation was composed of 151 major

depressed and 111 bipolar patients, treated with

fluvoxamine for a period of 6 wk. In this sample, the

depressed patients responded to treatment indepen-

dently from 5-HT1A variants, whereas, in the bipolar

sample, HTR1A C/C genotype carriers showed a

better response to fluvoxamine.

In a interesting recent study, Kraus and colleagues

reported that interferon therapy associated with

depressive episode was found to be related to the

G-allele homozygosity of the C(-1019)G variant (Kraus

et al., 2007), whereas 5-HT promoter (SLC6A4 or

5-HTTLPR) or tryptophan hydroxylase 2 (TPH2) gene

variations were not associated with such an important

iatrogenic effect.

Finally, in 40 remitted mood disorders patients,

C/C genotype carriers had lower scores at TCI (tem-

perament and character inventory) subscales of total

transcendence, transpersonal identification and spiri-

tual acceptance (items, or item clusters) (Lorenzi et al.,

2005), this finding agrees with a converging imaging

study (Borg et al., 2003).

There are other gene variations that have been in-

vestigated as relevant for the antidepressant response:

in 2004 Suzuki and colleagues (Suzuki et al., 2004)

found that the Gly272Asp variant could influence flu-

voxamine response in a sample of 65 depressed

patients being Asp allele-associated with higher

Hamilton Depression Rating Scale (HAMD) score re-

ductions after 2, 6 and 12 wk of treatment. Conflicting

with this, lack of association between fluvoxamine re-

sponse and the Gly272Asp variant was found in a

sample of 222 Chinese major depressive patients (Yu

et al., 2006), even though the C(-1019)G variant, which

was reported as in strong linkage disequilibrium (LD)

with Gly272Asp, showed a significant association in

the female group; C carriers having better clinic re-

sults after fluvoxamine treatment. This observation

raises the issue of LD calculation, in fact in the paper

the authors define strong LD based on a highD’, while

the r2 low value (less sensitive to low frequencies and

small sample sizes) indicated a marginal LD. There-

fore it is not surprising to observe discrepant findings

between variants.

As far as Caucasian samples are considered, the

positive association studies by Parsey and colleagues

are based on small sample size (cases n=22 and n=28)

(Parsey et al., 2006a,b) : this is an important limitation.

Moreover, the significant result by Parsey et al. (2006a)

was found in genotype distribution within remitters

and the control group (p=0.005), while no significant

difference was found between remitters and non-

remitters (p=0.073). Analysis on allele distribution

reported non-significant results (p=0.058). Moreover,

the positive study by Arias and colleagues (Arias et al.,

2005) considered a sufficient sample size (cases

n=130) but revealed significant association between

5-HT1A genetic variations and antidepressant response

only after considering the genetic variation of the

HTR1A together with the functional polymorph-

ism in the promoter of the serotonin transporter

(HTTLPR), prompting the hypothesis that the statisti-

cal significance is mostly based on the latter. This is

consistent with the negative results our group re-

ported about Caucasian samples (Mandelli et al., 2006;

Serretti et al., 2004) together with other negative find-

ings obtained by other groups (Peters et al., 2004). The

positive findings reported in Asian samples (Hong

et al., 2006; Suzuki et al., 2004; Yu et al., 2006) could

be explained by the different prevalence of the in-

vestigated polymorphisms between different ethni-

cities. Another possible reason to explain conflicting

results is that complex phenotypes can not be ex-

plained by single gene mutations: considering haplo-

types involving different genes within the 5-HT

708 A. Drago et al.


system and beyond it, could be a good strategy. The

previously mentioned paper by Arias et al. (2005)

stressed this line of research. Finally, a more complete

investigation of the all the single gene variants is sug-

gested.

Suicide

Table 4 gives a list of studies dealing with suicidal

behaviour in association with 5-HT1A genetic variants.

The main results and significance are reported.

The C(-1019)G variant has been associated with

suicidal behaviour, even though there is also conflict-

ing evidence and generally this variant together with

the structural Gly272Asp and Pro16Leu variants

do not seem to be strongly associated with suicide

behaviour or attempt. In a recent study we performed

(Serretti et al., 2006), no significant association

was found between 5-HT1A variants and suicide.

Wassermann and colleagues (2006) had similar

results in a sample of 272 suicide attempter families :

the HTR1A promoter variant seemed to be not as-

sociated with suicide history except for a trend of

G allele over transmission in a subgroup of suicide

attempters characterized by high levels of traumatic or

stressful life events prior to the suicide attempt.

Interestingly, stressful life events were not found to

be associated with HTR1A variants and mood dis-

orders in a large Italian sample (n=686) recently in-

vestigated by our group (Mandelli et al., 2006). Those

lines of evidence taken together might suggest that

suicide could be associated with the HTR1A promoter

polymorphism and stressful life events independently

from mood disorders. A stronger boundary with

the impulsiveness cluster, might be a possible hy-

pothesis.

Other negative association results can be found in

some studies considering the promoter or the struc-

tural polymorphisms (Huang et al., 2004; Nishiguchi

et al., 2002; Ohtani et al., 2004; Videtic et al., 2006).

Positive association findings are also available

(Lemonde et al., 2003). Again, a possible explanation

of non unequivocal evidence could be addressed to

incomplete gene polymorphism analysis, to the un-

known and probably multifactorial pathogenesis of

psychiatric disorders, and to the small impact of a

single gene in such complex phenotypes (Kendler,

2005). According to the last point, an interesting study

performed by Hsiung and colleagues (2003) reported

that at least two independent second-messenger cas-

cades after 5-HT1A activation in the brain of suicide

victims were differently active when compared with

controls, this suggests that future studies should con-

sider complex haplotypes, choosing them on the basis

of evidence and rational study of internal cell mech-

anisms.

Anxiety disorders

Table 5 gives a list of studies dealing with anxiety

disorders in association with 5-HT1A genetic variants.

The main results and significance are reported. Several

lines of evidence show a significant relationship be-

tween 5-HT1A and anxiety symptoms.

Table 4. Suicide


Serretti et al. (2006) C(-1019)G 411 Caucasian suicide attempters No significant association Not significant

rs1423691 443 controls

rs878567

Wasserman et al.

(2006)

C(-1019)G 272 Caucasian suicide attempter families G allele overtransmitted

in a subgroupa

p=0.0630

Videtic et al. (2006) C47T 226 Caucasian suicide victims 225

Caucasian healthy control subjects


G815A

Huang et al. (2004) C(-1019)G 696 psychiatric subjects of different

ethnicities


241 post-mortem brain cases

107 healthy volunteers

Ohtani et al. (2004) Pro16Leu 134 Japanese suicide victims No significant association Not significant

325 Japanese controls

Nishiguchi et al.

(2002)

Pro16Leu 163 Japanese suicide completers No significant association Not significant

Gly272Asp 163 Japanese controls

a High level of previous traumatic and/or stressful life events.



Animal experiments show anxiety-like behaviour in

5-HT1A knockout rats (Groenink et al., 2003; Heisler

et al., 1998; Olivier et al., 2001; Parks et al., 1998;

Parsons et al., 2001; Ramboz et al., 1998; Toth, 2003),

probably because of a perturbation in the prefrontal

GABA/glutamate system (Bruening et al., 2006).

Moreover, severe acute stress as well as stress of 2 wk

duration has been found to be associated with down-

regulation of 5-HT1A mRNA synthesis in the rat hip-

pocampus (Lopez et al., 1998, 1999). Neumeister and

colleagues consistently reported lower 5-HT1A density

in the anterior cingulate, posterior cingulate and raphe

of patients suffering from panic disorders with or

without depressive comorbidity (Neumeister et al.,

2004). Anti-anxiety properties of 5-HT1A active drugs

are well known in everyday clinical practice. Con-

sistent with this, panic disorder was recently found

to be associated with HTR1A and COMT variants

(Freitag et al., 2006), and when HTR1A is considered

alone, a significant relationship is still found between

the promoter polymorphism and panic (Huang et al.,

2004; Rothe et al., 2004). Those findings seem to be

more significant when panic with agoraphobia is con-

sidered, prompting the idea that a more in-depth dis-

section of clinical phenotypic subtypes would be a

good strategy for future investigations. Post-traumatic

stress disorder (PTSD) does not seem to be associated

with 5-HT1A density variants (Bonne et al., 2005).

There is a lack of evidence regarding other anxiety

disorders.

Bipolar disorder

Imaging studies investigating the hypothesis of a

different density or affinity of 5-HT1A receptors in

hippocampal and cortex regions reported negative

findings (Dean et al., 2003; Gray et al., 2006), even

though an interesting dissociation between the num-

ber of receptors and the activity of G protein-

associated second-messenger cascade was reported in

the study performed by Gray and colleagues: this

could suggest a kind of segregation of 5-HT1A re-

ceptors leading to a normal number of receptors as-

sociated with a reduced activity in bipolar disorder. In

the same study a gender difference was reported, i.e.

5-HT1A receptors were expressed less in female brains

(Gray et al., 2006). A mRNA in-situ hybridization

study confirmed this report (Lopez-Figueroa et al.,

2004).

Conflicting with this, some animal studies in-

vestigated the possible role of 5-HT1A receptors in the

pharmacodynamics of mood stabilizers, reporting

positive association results. Lithium was found to en-

hance the sensitivity of post-synaptic 5-HT1A after

short-term administration (Blier et al., 1987). This

finding was replicated by Haddjeri and colleagues

(2000) : lithium augmentation of long-term anti-

depressant treatment in rats was found to be as-

sociated with an enhanced disinhibition of dorsal

hippocampal CA3 pyramidal neurons, an action

which is known to be mediated by post-synaptic

5-HT1A receptors. More recently, McQuade and col-

leagues reported an association with chronic lithium

treatment and reduced 5-HT1A mRNA in the hippo-

campus, whereas no different levels of 5-HT1A mRNA

could be found in the dorsal raphe nucleus where

5-HT1A receptors are present as autoreceptors

(McQuade et al., 2004). Post-synaptic 5-HT1A receptors

were found to be influenced also by lamotrigine,

another mood stabilizer (Bourin et al., 2005), whereas

Table 5. Anxiety


Freitag et al.

(2006)

C(-1019)G 115 Caucasian patients

suffering from panic attacks

GG genotype associated with panic

when considered together with

COMT polymorphism

p=0.04


Rothe et al.

(2004)

C(-1019)G 134 Caucasian patients suffering

from panic attacks with (n=101)

or without agoraphobia

G allele associated with panic

disorder with agoraphobia

p=0.03


Huang et al.

(2004)

C(-1019)G 696 psychiatric subjects

of different ethnicities

G associated with schizophrenia,

substance use and panic attack

p=0.009

p=0.015



No significant association result in

post-mortem brain (mRNA levels

and genotype)

p=0.043

respectively

710 A. Drago et al.


negative findings were reported for valproate (Delva

et al., 2002; Khaitan et al., 1994). As mentioned

previously, in our 2004 study, we reported that

HTR1A C/C bipolar genotype carriers showed a bet-

ter response to fluvoxamine in regard to depressive

episodes (Serretti et al., 2004). Those lines of evidence

could suggest a possible pharmacological impact of

5-HT1A gene variants, but more studies and a larger

gene investigation are needed in this field of research.

Psychosis

Table 6 gives a list of studies dealing with psychotic

disorders in association with 5-HT1A genetic variants.

The main results and significance are reported.

5-HT1A seems to be highly involved in the patho-

logical neurotransmitter disequilibrium associated

with schizophrenia. Several post-mortem brain stud-

ies reported HTR1A altered expression in schizo-

phrenia patients (see Frankle et al., 2006 for a review),

and, consistent with this, two PET studies (Kasper

et al., 2002; Tauscher et al., 2002) reported increased

5-HT1A density in prefrontal and temporal cortices,

whereas a diminished density in amygdala or no dif-

ferent density compared to controls were found in

other PET studies (Frankle et al., 2006; Yasuno et al.,

2004). This diversity could be due to the different res-

olution of post- mortem and PET studies: only the

former can investigate the 5-HT1A density in different

layers of brain tissues.

Besides conflicting imaging studies, there is evi-

dence that 5-HT1A is involved in antipsychotic re-

sponse. Many atypical antipsychotics act on 5-HT1A

(clozapine, serizotan, bifeprunox, nomonapride, zi-

prasidone, aripiprazole, tiospirone) and even though

other atypicals such as olanzapine or risperidone are

not directly active on 5-HT1A, it has been suggested

that the improvement of depressive symptomatology,

which is characteristic of atypical antipsychotics,

could be associated with a dopamine-enhanced re-

lease in the mPFC, this being dependent also on

5-HT1A activity (Ichikawa et al., 2001; Newman-

Tancredi et al., 2005). The role of 5-HT1A receptors in

antipsychotic treatment, especially as far as negative

symptomatology is concerned, is suggested by

Richtand and colleagues who recently reported that

the strongest correlation with clinically effective drugs

and receptor activity profile is the HTR2C/D2 ratio for

the typical antipsychotics, and HTR2A/5-HT1A and

HTR2C/5-HT1A for the atypical antipsychotics : the

higher the 5-HT1A expression or function, the less ef-

fective the antipsychotic treatment (Richtand et al.,

Table 6. Psychosis


Huang

et al. (2004)

C(-1019)G 696 psychiatric subjects of

different ethnicities

G associated with schizophrenia,

substance use and panic attack

p=0.009

p=0.015



No significant association result

in post-mortem brain (mRNA

levels and genotype)

p=0.043

respectively

Reynolds

et al. (2006)

C(-1019)G 63 drug naive Caucasian

psychotic patients treated

with antipsychotic for 3 months

G allele associated with worse

response to treatment (negative

symptoms)

p=0.001

Lane et al. (2006) Gly272Asp 123 Han Chinese psychotic

patients treated with

risperidone

No association with psychotic

symptoms

Not significant

Serretti et al.

(2000)

Ile28Val 72 Caucasian bipolar patients No association with psychotic

symptoms

Not significant

12 Caucasian depressed patients

Erdmann

et al. (1995)

Ile28Val 352 Caucasian schizophrenic No significant association Not significant


Kawanishi

et al. (1998)

Gly272Asp 61 Japanese schizophrenic No significant association Not significant

Pro16Leu 100 Japanese controls

C-51T

G-152C

C-321G

-480delA,

A-581C



2007). Moreover, Cosi and colleagues reported that

atypical antipsychotics that are active on 5-HT1A, but

not haloperidol which is devoid of 5-HT1A, were as-

sociated with a reduced kainite-induced brain damage

in rats (Cosi et al., 2005). This is quite interesting be-

cause of the possible neurodegenerative aetiopatho-

genesis of schizophrenia, and the suggestion of a

possible use of 5-HT1A agonists as protectors against

excitotoxic injuries.

In regard of the benefit over negative symptoma-

tology, Sato and colleagues recently reported that ris-

peridone can increase acetylcholine release (which is

assumed to be associated with cognitive performance),

in the PFC of rats through a complex mechanism

enhanced by 5-HT1A activation: if its activation is

missing, the acetylcholine levels in prefrontal brain

structures are impaired after risperidone treatment,

whereas the simple 5-HT1A stimulation does not alter

acetylcholine levels in the brain (Sato et al., 2007). The

same result was obtained by Chung and colleagues in

2004, using clozapine (Chung et al., 2004). This is

consistent with other papers which reported the as-

sociation of 5-HT1A with cognitive functions

(Sumiyoshi et al., 2000; Sumiyoshi and Meltzer, 2004;

Tamminga, 2006). The benefit on antipsychotic-

induced motor side-effects could be also partially

associated with 5-HT1A function when atypical anti-

psychotics are used: it has been proposed that the

serotonergic modulation over dopaminergic system is

principally inhibitory, thus, the stimulation of pre-

synaptic 5-HT1A should lead to an inhibitory effect

over HTR2C which in dopaminergic neurons will lead

to a final effect of diminished inhibition and a benefit

for movement dyscontrol (Haleem, 2006).

Other evidence of 5-HT1A modified function in

schizophrenia comes from a study by Lee and Meltzer

(2001) reporting that 5-HT1A functionality is impaired

in schizophrenic females: the plasma cortisol concen-

tration increased after ipsapirone administration was

found to be blunted in schizophrenic female patients.

Other parameters such as hypotermina, nausea, diz-

ziness, irritability, and feeling less well did not differ

between schizophrenic and healthy subjects. It must

be underlined that the blunted plasma cortisol con-

centration stands for a hypofunction of 5-HT1A post-

synaptic receptors (Lee and Meltzer, 2001).

Even though all these lines of evidence should en-

courage investigations on HTR1A variants, there are

not many studies investigating 5-HT1A genetic vari-

ants and the study of clinical characteristics of

schizophrenia or schizophrenia-like disorders.

In 2004 Huang and colleagues (Huang et al., 2004)

reported that the C(-1019)G variant was associated

with schizophrenia together with substance use dis-

order and panic attacks, this result was replicated 2 yr

later by Reynold and colleagues (2006) who reported

that C/C carriers had better scores at PANSS (Positive

and Negative Syndrome Scale), but not for positive

symptoms, and at the Calgary Depression Scale than

G/G carriers after 3 months of a standard treatment

for acute psychosis. Interestingly, with the Calgary

Depression Scale G/G carriers showed worse con-

ditions at the end of treatment than at the beginning.

This is consistent with the literature findings dis-

cussed above about HTR1A variant and depression.

In 2006 Lane and colleagues investigated the hy-

pothesis that HTR1A variants, together with another

15 genetic variants across 10 candidate genes [5-HT1A,

5-HT2A, 5-HT2C, 5-HT6, D1, D2, D3, a1-adrenergic re-

ceptors, brain-derived neurotrophic factor (BDNF),

and cytochrome P450 2D6], could influence the ris-

peridone-associated weight gain side-effect. A sample

of 122 Han Chinese schizophrenia in-patients was

selected: the HTR1A Gly272Asp variant showed no

evidence of association (Lane et al., 2006). Finally, our

group investigated the Ile28Val polymorphism of the

5-HT1A coding sequence in a sample of 84 in-patients

affected by mood disorders (72 bipolar and 12 major

depressive disorder) verifying the hypothesis that

5-HT1A could be involved in psychotic symptoms of

mood disorders. No association result was found

(Serretti et al., 2000). The different ethnicity of the

samples investigated [Caucasians (Erdmann et al.,

1995; Huang et al., 2004; Reynolds et al., 2006; Serretti

et al., 2000) and Asians (Kawanishi et al., 1998; Lane

et al., 2006)], could explain the inconsistency of results.

As far as the study on the bipolar sample is concerned

(Serretti et al., 2000), the different psychiatric disorders

at the basis of the investigation, is probably the most

important cause of discrepancy.

The Ile28Val variant was also investigated in a large

case (n=352) control (n=210) study with no evidence

of association with schizophrenia. The sample also

included other diagnoses such as bipolar disorder and

Tourette’s syndrome (Erdmann et al., 1995). Lack of

association within HTR1A variants and schizophrenia

was also reported by Kawanishi and colleagues

(1998) : in this work a list of variants was considered

[Gly272Asp, Pro16Leu, A(294)G, T(549C), C(51T),

G(-152)C, C(-321)G, (-480)delA, and A(-581)C]. So

far, studies investigating the C(-1019)G variant tended

to find positive association results in Caucasian

samples. The other considered variants tended to give

negative association results. Study designs involving

all the known and validated genetic variants of 5-HT1A

are missing.

712 A. Drago et al.


Other findings

Anxiety, as measured by the NEO Personality

Inventory, showed a negative association with 5-HT1A

density in a PET study performed in a sample of 19

healthy volunteers (Tauscher et al., 2001). In another

PET study, the 5-HT1A density was found to be

negatively correlated with spiritual acceptance, a

sub-item of the TPQ (Tridimensional Personality

Questionnaire) in 15 healthy subjects (Borg et al.,

2003), and in 2005 our group investigated this field

from a genetic point of view, finding that C/C carriers

at the C(-1019)G variant were more likely to have sig-

nificantly lower scores at the total self-transcendence

and at the subscales of transpersonal identification

and spiritual acceptance (Lorenzi et al., 2005). Finally,

an association study considering personality traits and

the C(-1019)G HTR1A promoter variant in 284 healthy

students, reported an association with the G allele and

higher scores on the neuroticism scale on the NEO

Personality Inventory and more harm avoidance on

the TPQ (Strobel et al., 2003).

SNP suggestion

As previously seen, not all the validated SNPs of the

HTR1A sequence have been investigated over the re-

viewed studies. This is an important methodological

bias. A complete and commonly accepted investi-

gation of the gene is advised for the following reasons:

(1) to facilitate the interpretation of results throughout

different studies ;

(2) to cover important functional areas such as 5k-UTR,

3k-UTR, promoter, enhancers, silencers;

(3) to permit an inductive research approach to the

genetic sequence, identifying relevant mutations

still to be hypothesized;

(4) to permit the identification of mutations interfering

with important functional mechanisms such as:

DNA access, reading and transduction, mRNA

stability and translation, mRNA primary structure-

based functions. In all those mechanisms, intronic

sequences are as important as exonic ones.

Actual genome-wide techniques make it possible to

investigate several polymorphisms (up to 600 000) in a

single investigation scan, and the costs have started to

decrease substantially, not least because of compe-

tition between the leading commercial platforms,

Illumina and Affymetrix. This offers a unique oppor-

tunity to investigate haplotypes in a complete way. As

far as 5-HT1A is concerned, its possible involvement in

psychiatric disorders, following evidence of animal

and imaging studies, should be investigated at least

through all the validated variants. A list of validated

SNPs covering all of the gene is presented in Table 1;

data are collected from international databases

(http://www.ncbi.nlm.nih.gov/). To select the SNPs

two filters have been applied: complete coverage of the

gene and validation status. The first point has been

discussed previously. Validation status is advised

because it would be clinically useful and statistically

advisable, to concentrate research on genetic variants

that have a sufficient chance to be detected in the

general population. Table 1 gives the list of selected

variants with allele prevalence information.

Conclusions

Research suggesting that association studies may have

success in finding complex trait genes (De La Vega

et al., 2005; Risch and Merikangas, 1996) and the dis-

covery and validation of large numbers of SNPs in the

human genome (HapMap, 2003), have elicited a

growing interest in the performance of large-scale

genetic association studies using SNPs at the candi-

date-gene, whole-chromosome, and eventually whole-

genome level (De La Vega et al., 2005).

Genetic association studies require a large sample

size and strict investigation methodologies (Risch

andMerikangas, 1996) given that the reliably observed

gene variants odd ratios range around 1.2–1.5

(Kendler, 2005; Lasky-Su et al., 2005). The most part of

published work does not reach the theoretical meth-

odology threshold. It has recently been demonstrated

that going genome-wide makes the sample size a pre-

dominant determinant of the feasibility of the studies.

A number of 1.000 subjects per arm is advised for

common causal alleles with relatively large effect sizes

[genotype relative risk (GRR) 1.7] (Nannya et al.,

2007). Further, the definition of GRR depends also on

the disease model. If f0, f1, f2 are the probabilities of

being affected for individuals with 0, 1, or 2 copies of

the risk allele, then GRR can be: multiplicative

(GRR=f1/f0=f2/f1), additive (GRR=f1/f0), domi-

nant (GRR=f1/0=f2/f0), recessive (GRR=f2/f0=f2/

f1) (http://csg.sph.umich.edu/). Even though most

SNPs are believed to have a co-dominant, additive

effect, other models have been also proposed

(Greenberg et al., 1999; Hranilovic et al., 2004; Lesch,

2001).

However, as a practical example, using an additive

model and considering the prevalence of rs6295

(C(-1019)G), a sample size of 600 cases and 600 con-

trols is needed to obtain a power of 80% (one-stage

design) with a quite liberal p of 0.01 to detect and odds



ratio of 1.5. For the rarest Ile28Val mutant allele, a

total sample size of over 50 000 subjects is needed!

(Cohen, 1988). This simulation is driven on the basis of

the investigation of a single gene, which is the most

common path in the reviewed papers. Consideration

of haplotypes further complicates the interpretation

of results given the risk of false positives and non-

independent observation (Purcell et al., 2003; Purcell

and Sham, 2001).

None of the studies reviewed in the present paper

reached the theorically requested sample size for the

investigated mutations. Moreover, many stratification

factors such as ethnicity, sociodemographic and clini-

cal issues, different treatment, different period of

treatment, different study design, multicentre vs.

monocentre investigations, different age of onset, pre-

vious treatments, comorbidity and other important

variables generally influence the validity of results.

A large part of this methodological issue has been

recently summarized and critically reviewed by our

group regarding pharmacogenetics (Serretti et al.,

in press) and may be responsible for inconclusive

findings even in very large sample sizes (Lewis et al.,

2003; Segurado et al., 2003; Wellcome Trust, 2007).

However, beyond clinical and endophenotipic dis-

sections, one important and easy-to-fix bias is the

complete gene variant coverage. In fact, 5-HT1A gene

variants have been reported to play some role in as-

sociation with psychiatric disorders such as mood

disorders, anxiety disorders and psychotic disorders,

but the literature findings are not unequivocal. The

C(-1019)G variant seems to be of primary interest in

antidepressant response, and preliminary studies

seem to indicate a role for 5-HT1A gene variants in

the psychotic spectrum but the evidence remains weak

and difficult to decipher. We suggest that genetic as-

sociation research would be reasonably more efficient

if all the validated SNP variants were included, this

point is easy to accomplish and technically feasible.

Acknowledgements

None.

Statement of Interest

None.

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5-ht1a gene variants and psychiatric disorders: a review of current

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