biostudies-literatureRussell MLNational Institute of Allergy and Infectious DiseasesHoward Hughes Medical InstituteNIAID NIH HHSNational Heart, Lung, and Blood InstituteNHLBI NIH HHSNational Cancer InstituteNCI NIH HHSNational Institutes of HealthNIH HHSThe Simons Foundation and Howard Hughes Medical Institutee73475https://www.ebi.ac.uk/biostudies/studies/S-EPMC8940181biostudies-literatureUnknown11Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individual's genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the <i>TCRB</i> locus and, specifically for the functional TeLifeCombining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities.PMC8940181HL088201R01 HL087690R01 AI107625R01 HL094260AI33484HL087690InvestigatorCA015704P01 AI033484HL09426055108544S10 OD028685HHSN272201400006CR01 HL088201HL105914R01 AI136514P30 CA015704K23 HL069860AI149213R01 AI120997R01 AI14602875N93021C00016HHSN272201 400006CR01 HL105914K23HL69860Russell MLBradley PBalmaseda ASimon NLevine DMAllen EKMatsen FAKuan GSouquette ASchattgen SAThomas PGGordon AfalseCombining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities.Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individual's genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the <i>TCRB</i> locus and, specifically for the functional T2022-01-01T00:00:00Z2022 Mar2026-05-31T16:11:01.587Z2024-11-09T02:09:21.502ZS-EPMC89401813531577010.7554/eLife.73475