The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.

Department of Microbiology and Immunology Drexel University College of Medicine Philadelphia PA 19129 USA

Department of Psychiatry New York University School of Medicine New York City NY 10016 USA

Department of Psychiatry Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

Department of Surgery University of Alabama at Birmingham Birmingham AL 35294 USA

Laboratory of Neuroimaging National Institute on Alcohol Abuse and Alcoholism Bethesda MD 20817 USA

Laboratory of Psychiatric Neurogenomics McLean Hospital and Department of Psychiatry Harvard Medical School Belmont MA 02478 USA

Molecular Neurosciences Developmental Neurosciences Zayed Centre for Research into Rare Diseases in Children UCL Great Ormond Street Institute of Child Health and Department of Neurology Great Ormond Street Hospital London WC1N 1EH UK

National Institute on Drug Abuse Bethesda MD 20817 USA

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