Serotonin transporter gene (SLC6A4) polymorphism and susceptibility to a home-visiting maternal-infant attachment intervention delivered by community health workers in South Africa: Reanalysis of a randomized controlled trial

B. Morgan, R. Kumsta, P. Fearon, D. Moser, S. Skeen, P. Cooper, L. Murray, G. Moran, M. Tomlinson

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Background: Clear recognition of the damaging effects of poverty on early childhood development has fueled an interest in interventions aimed at mitigating these harmful consequences. Psychosocial interventions aimed at alleviating the negative impacts of poverty on children are frequently shown to be of benefit, but effect sizes are typically small to moderate. However, averaging outcomes over an entire sample, as is typically done, could underestimate efficacy because weaker effects on less susceptible individuals would dilute estimation of effects on those more disposed to respond. This study investigates whether a genetic polymorphism of the serotonin transporter gene moderates susceptibility to a psychosocial intervention. Methods and findings: We reanalyzed data from a randomized controlled trial of a home-visiting program delivered by community health workers in a black, isiXhosa-speaking population in Khayelitsha, South Africa. The intervention, designed to enhance maternal-infant attachment, began in the third trimester and continued until 6 mo postpartum. Implemented between April 1999 and February 2003, the intervention comprised 16 home visits delivered to 220 mother–infant dyads by specially trained community health workers. A control group of 229 mother–infant dyads did not receive the intervention. Security of maternal-infant attachment was the main outcome measured at infant age 18 mo. Compared to controls, infants in the intervention group were significantly more likely to be securely attached to their primary caregiver (odds ratio [OR] = 1.7, p = 0.029, 95% CI [1.06, 2.76], d = 0.29). After the trial, 162 intervention and 172 control group children were reenrolled in a follow-up study at 13 y of age (December 2012–June 2014). At this time, DNA collected from 279 children (134 intervention and 145 control) was genotyped for a common serotonin transporter polymorphism. There were both genetic data and attachment security data for 220 children (110 intervention and 110 control), of whom 40% (44 intervention and 45 control) carried at least one short allele of the serotonin transporter gene. For these 220 individuals, carrying at least one short allele of the serotonin transporter gene was associated with a 26% higher rate of attachment security relative to controls (OR = 3.86, p = 0.008, 95% CI [1.42, 10.51], d = 0.75), whereas there was a negligible (1%) difference in security between intervention and control group individuals carrying only the long allele (OR = 0.95, p = 0.89, 95% CI [0.45, 2.01], d = 0.03). Expressed in terms of absolute risk, for those with the short allele, the probability of secure attachment being observed in the intervention group was 84% (95% CI [73%, 95%]), compared to 58% (95% CI [43%, 72%]) in the control group. For those with two copies of the long allele, 70% (95% CI [59%, 81%]) were secure in the intervention group, compared to 71% (95% CI [60%, 82%]) of infants in the control group. Controlling for sex, maternal genotype, and indices of socioeconomic adversity (housing, employment, education, electricity, water) did not change these results. A limitation of this study is that we were only able to reenroll 49% of the original sample randomized to the intervention and control conditions. Attribution of the primary outcome to causal effects of intervention in the present subsample should therefore be treated with caution. Conclusions: When infant genotype for serotonin transporter polymorphism was taken into account, the effect size of a maternal-infant attachment intervention targeting impoverished pregnant women increased more than 2.5-fold when only short allele carriers were considered (from d = 0.29 for all individuals irrespective of genotype to d = 0.75) and decreased 10-fold when only those carrying two copies of the long allele were considered (from d = 0.29 for all individuals to d = 0.03). Genetic differential susceptibility means that averaging across all participants is a misleading index of efficacy. The study raises questions about how policy-makers deal with the challenge of balancing equity (equal treatment for all) and efficacy (treating only those whose genes render them likely to benefit) when implementing psychosocial interventions.
Original languageEnglish
Article numbere1002237
Number of pages19
JournalPLoS Medicine
Issue number2
Publication statusPublished - 28 Feb 2017

Bibliographical note

Cited By :5

Export Date: 29 May 2019

Correspondence Address: Morgan, B.; Global Risk Governance Programme, Institute for Safety Goverance and Criminology, Law Faculty, University of Cape TownSouth Africa; email:

Chemicals/CAS: Serotonin Plasma Membrane Transport Proteins; SLC6A4 protein, human

Funding details: Grand Challenges Canada, 0066-03

Funding text 1: This study was supported by a grant from Grand Challenges Canada (, grant reference #0066-03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to acknowledge all the parents and adolescents who participated in the study.

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  • serotonin transporter
  • SLC6A4 protein, human
  • adult
  • Article
  • community care
  • controlled study
  • evaluation and follow up
  • female
  • gene frequency
  • genetic polymorphism
  • genetic susceptibility
  • genotype environment interaction
  • genotype phenotype correlation
  • genotyping technique
  • geographic distribution
  • health care personnel
  • health program
  • human
  • intervention study
  • logistic regression analysis
  • major clinical study
  • male
  • middle aged
  • mother fetus relationship
  • outcome assessment
  • polymerase chain reaction
  • pregnancy
  • randomized controlled trial
  • reliability
  • sensitivity analysis
  • socioeconomics
  • South Africa
  • young adult
  • adolescent
  • behavior therapy
  • follow up
  • genetics
  • health auxiliary
  • metabolism
  • mother child relation
  • object relation
  • postnatal care
  • procedures
  • psychology
  • Adolescent
  • Behavior Therapy
  • Community Health Workers
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Mother-Child Relations
  • Object Attachment
  • Polymorphism, Genetic
  • Postnatal Care
  • Serotonin Plasma Membrane Transport Proteins
  • Socioeconomic Factors


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