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Within the <jats:italic>5-HTTLPR<\/jats:italic> polymorphism, a SNP (rs25531) in the L-allele in the promoter region, affects the transcription efficacy of the <jats:italic>SCL6A4<\/jats:italic>, leading to functionally important differences related to serotonin transporter availability in the synapses. <jats:italic>5-HTTLPR<\/jats:italic> has been implicated in magnitude of negative attentional bias, a causal risk factor for depression, and the modifiability of attentional biases both in positive and negative directions. Hence, this genotype may moderate the outcomes of attention bias modification (ABM) targeted at reducing depressive symptoms. We conducted a registered randomized sham-controlled trial of ABM in a sample of 301 participants with a history of Major Depressive Disorder (MDD) who had residual symptoms. They were randomized and underwent 14 days of two daily session of either ABM or sham at home. Of these, 264 provided genetic samples for determining the functionally important variant of the gene <jats:italic>SLC6A4<\/jats:italic>. We investigated if the SNP (<jats:italic>rs25531<\/jats:italic>) moderated the effect of ABM on symptoms of depression (HDRS, BDI-II) and anxiety (BAI), and attention bias post-intervention. None of the outcomes were moderated by the allelic variation in the promoter region of <jats:italic>5-HTTLPR<\/jats:italic>. Limitations include low level of depressive symptoms, lack of data on ethnicity, current and prenatal level of stress, and early traumatic experiences. The <jats:italic>5-HTTLPR<\/jats:italic> polymorphism did not moderate the effect of ABM on the symptom scales, nor attentional bias. Combination or interactions with other genes may be required for prescribing personalized interventions.<\/jats:p>","DOI":"10.1038\/s41398-025-03581-3","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T06:30:23Z","timestamp":1759732223000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["5-HTTLPR does not moderate the effect of attention bias modification for depression: a randomized sham-controlled trial"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3809-3084","authenticated-orcid":false,"given":"Ragnhild","family":"B\u00f8","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rune","family":"Jonassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1609-8335","authenticated-orcid":false,"given":"Catherine J.","family":"Harmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8yvind","family":"\u00d8verli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde Loge","family":"Nilsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q. 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