Genetic Determinants Of Major Depressive Disorder (MDD) Among Adult Persons Living With HIV In Uganda.

BackgroundMajor Depressive Disorder is complex and moderately heritable, with heritability estimates ranging from 30% to 40%. Major depressive disorder (MDD) is a significant comorbidity in people living with HIV (PLWHIV), where it is associated with non-adherence to anti-retroviral treatment, increased risk of suicide-related behaviors among others. This study investigated the genetic risk loci associated with MDD among adult PLWHIV in Uganda. MethodsThe case-control study analyzed 282 samples (139 MDD cases and 143 controls), who were assessed for MDD using the Mini International Neuropsychiatric Interview. The DNA of study participants was genotyped at the Center for Proteomic and Genomic Research in South Africa using the H3Africa array (version2). Data were analyzed using PLINK2 and GEMMA softwares for quality control and genome-wide association analysis respectively, followed by functional mapping with FUMA software. ResultsWhile no significant single nucleotide polymorphisms (SNPs) were identified at the genome-wide threshold, three independent SNPs were found to be suggestively associated with MDD with the most significant being rs4375916 on chromosome 2 (p=1.086x10-7), followed by rs1075618 on chromosome 3 (p=3.093x10-7) and rs953855 on chromosome 13 (p=4.906x10-7). These SNPs have been found to be linkage disequilibrium (LD) with SNPs previously associated with other psychiatric conditions like Alzheimers, alcohol use disorder, and bipolar disorder, although they have not previously been linked to MDD. Gene-set enrichment analysis revealed associations with key biological processes including synaptic organization suggesting potential involvement in the pathophysiology of MDD. ConclusionThis study provides preliminary evidence for genetic contributors to MDD in PLWHIV of African ancestry. While larger, adequately powered studies are needed, our findings emphasize the importance of investigating psychiatric genetics in HIV populations, where depression represents a critical comorbidity influencing treatment outcomes.