Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy

Figures & data

Table 1 Notable studies reporting the association of the 5-HTTLPR polymorphism to psychopathology

Psychopathology	Reference	n	Risk allele	Comment
Anxiety	Lesch et al^Citation4	505	S	Genotype contributes 3%–4% of total variation and 7%–9% of genetic variance in anxiety-related personality traits
	Hariri et al^Citation6	28	S	Increased amygdala activity in response to fearful stimuli
	Heinz et al^Citation17	29	S	Increased amygdala activity in response to aversive but not pleasant pictures
	Surguladze et al^Citation18	29	S	Genotype affects amplitude of neural response and connectivity within the neural system
	Munafo et al^Citation19	NR	S	Meta-analysis; heightened amygdala activation; 10% of phenotypic variance
	Munafo et al^Citation20	3872	NS	Meta-analysis; no association with two measures of anxiety-related personality traits; results differ between personality inventories
Depression	Caspi et al^Citation7	847	S	G × E interaction with effect of stressful life events on depression risk; childhood maltreatment predicted adult depression in S carriers only
	Risch et al^Citation12	14,250	NS	Meta-analysis; no significant association with depression; no interaction with the effect of stressful life events on the risk of depression
	Coplan et al^Citation27	9	S	Bonnet macaques; elevated CRH in CSF of primate S carriers raised under stressful conditions
	Yu et al^Citation29	121	L/L	Better response to fluoxetine with L/L genotype; genotype predicted response; L homozygotes more likely to be responders
	Smeraldi et al^Citation30	102	L	L carriers demonstrated a greater response to fluvoxamine
	Zanardi et al^Citation33	60	L/L	Dose response: L/S genotype had response to paroxetine in between S and L homozygotes
	Pollock et al^Citation34	95	L/L	No genotype effect on response to nortriptyline; L/L genotype associated with quicker response to paroxetine
	Durham et al^Citation35	206	L/L	L/L genotype associated with quicker response to sertraline
	Huezo-Diaz et al^Citation37	795	L	The effect of 5-HTTLPR on response to escitalopram response was conditional on gender (males) and modulated by the rs2020933 polymorphism
	Serretti et al^Citation39	1435	L/L	Meta-analysis; poor response to SSRIs in S carriers; S allele-mediated effect on time-to-response; L/L genotype versus the L/S and S/S genotypes yielded significant odds ratios for response rate and response within four weeks
	Karg et al^Citation26	40,749	S	Meta-analysis; strong association between the 5-HTTLPR S allele and an increased risk of developing depression under stress. When specific stressors were considered, the strongest association was with the childhood maltreatment and the specific medical condition groups
	Taylor et al^Citation40	5408	NS	The 5-HTTLPR did not predict antidepressant outcome
	Lewis et al^Citation36	258 took citalopram 262 took reboxetine	NS	No influence of 5-HTTLPR as a predictor of depression outcome
Suicidal behavior	Du et al^Citation43,Citation44	55	L	Completed suicide victims had almost double the frequency of the L/L genotype than that of controls
	Russ et al^Citation45	102	NS	No significant difference in allele frequency; significantly increased hopelessness and suicidal ideation in patients homozygous for the L allele
	Anguelova et al^Citation46	2539	S	Meta-analysis; association attributable to studies investigating suicide attempters
Bipolar disorder	Cho et al^Citation48	4296 + 587 trios	S	Meta-analysis, population-based and family-based; increased susceptibility to BPD
	Anguelova et al^Citation49	3467	S	Meta-analysis; increased susceptibility to BPD
	Rotondo et al^Citation50	349	S	Association significant only for BPD without comorbid panic disorder versus BPD with comorbid panic disorder
	Mundo et al^Citation52	56	S	Association between S allele and manic/hypomanic episodes in BPD patients treated with antidepressants
PTSD	Lee et al^Citation55	297	S	Significantly higher frequency of the S-homozygous genotype in patients with PTSD
	Wang et al^Citation56	388	S′/S′	The S′-homozygous genotype was associated with the PTSD severity score in the 228 participants who had combat severity data
	Xie et al^Citation57	1252	S	S carriers have increased risk of PTSD in response to trauma as a child and adult
	Mushtaq et al^Citation59	330	L/L	L-homozygous is associated with greater responsiveness of PTSD to sertraline (100 mg/day) with lower drop out due to adverse events
	Grabe et al^Citation60	3045	LA	Gene-dose effect; interaction between the LA allele and number of traumatic life events
Alcohol dependence	Kweon et al^Citation64	346	L	Increased risk of alcoholism; gene-dose effect; younger age of onset; associated with family history of AD
	McHugh et al^Citation66	8050	S	Meta-analysis; greater effect seen in S homozygotes
	Ait-Daoud et al^Citation67	34	L	L carriers had higher craving than S/S; Craving in L carriers increased with an earlier age of onset of problem drinking
	Feinn et al^Citation69	5814	S	S allele significantly associated with AD; Greatest association between S allele and comorbid psychiatric condition, early-onset or more severe AD subtype
	Enoch et al^Citation70	547	NS	No significant association for AD only; Frequency of S allele significantly increased in patients with AD and comorbid drug dependence
	Matsushita et al^Citation8	967	S/S	S-homozygous genotype associated with binge drinking
	Kranzler et al^Citation75	101	TX	Increased alcohol consumption in EOAs with fluoxetine
	Pettinati et al^Citation76	100	NA	Increased alcohol consumption in EOAs with sertraline; decreased consumption in LOAs
	Kranzler et al^Citation77	134	L′/L′	In LA/LA (L′/L′) homozygotes, the effects of medication group varied by age of onset. LOAs with the L′/L′ alleles had fewer drinking and heavy drinking days with sertraline; EOAs had fewer drinking and heavy drinking days with placebo
	Johnson et al^Citation78	271	NR	Treatment with ondansetron increased the number and percentage of days abstinent in patients with EOA but not LOA
	Kenna et al^Citation72	15	L/L	L homozygotes receiving ondansetron had significantly fewer DDD than patients receiving sertraline
	Johnson et al^Citation82	283	L/L	L homozygotes who received ondansetron reported fewer mean drinks per drinking day and a higher percentage of days abstinent
Nicotine dependence ADHD	Kremer et al^Citation87	730	L	Frequency significantly increased in both current and past smokers compared with nonsmoker controls
	Thakur et al^Citation90	157	LA	LA carriers responded significantly better to methylphenidate than placebo; patients without a LA allele did not exhibit a significantly better response compared with placebo
	Seegar et al^Citation91	243	L/L	Frequency of L-homozygous genotype significantly increased in patients with hyperkinetic disorder both with and without conduct disorder
	Retz et al^Citation93	169	L/L	L homozygotes scored significantly higher on the WURS.
	Zoroğlu et al^Citation94	199	L	Frequency of S-homozygous genotype significantly lower in patients with ADHD

Abbreviations: AD, alcohol dependence; ADHD, attention deficit hyperactivity disorder; BPD, bipolar disorder; CRH, corticotrophin-releasing hormone; CSF, cerebrospinal fluid; DDD, drinks per drinking day; EOA, early-onset alcoholism; G × E, gene × environment; L, long 5-HTTLPR allele; LOA, late-onset alcoholism; NR, not reported; NS, not significant; PTSD, post-traumatic stress disorder; S. short 5-HTTLPR allele; SSRI, selective serotonin reuptake inhibitor; WURS, Wender Utah Rating Scale; 5-HTT, serotonin transporter.

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