OC 64.1 - The VarioPath project: Determining effect sizes of pathogenic variants in platelet disorder genes, using clinical data from 0.5M whole exome sequenced UK Biobank participants

Background: Accurate determination of the effect sizes of DNA variants causal of platelet disorders is essential for reliable reporting to clinicians and patients. However, this has only recently become feasible for rare variants, with the release of the whole-exome-sequencing (WES) and associated clinical data from 0.5 million UK Biobank (UKB) participants.

Aims: To calculate the effect sizes of rare pathogenic/likely pathogenic variants (P/LPVs) causal of autosomal dominant (AD)-platelet disorders and determine the clinical sequelae of carrying a single P/LPV causal of recessive (AR)-platelet disorders.

Methods: We identified 484 P/LPVs in platelet disorder genes, present in UKB WES data with a minor-allele-frequency < 0.001. Single-variant linear regression analysis calculated effect sizes of P/LPVs present in at least five out of 131,022 unrelated European UKB-participants, after adjusting for relevant covariates and genomic principle components (significance at P-value < 0.05 after Benjamini-Hochberg multiple-testing correction).

Results: Analysis of 19 P/LPVs for AD-thrombocytopenia revealed four that significantly reduce platelet count and increase mean platelet volume (MPV); the largest effect sizes were -1.4 SD for platelet count and 1.7 SD for MPV, for GP1BA:p.Gln196Ter, present in 19 UKB-participants. Three TUBB1-variants, together observed in 96 participants, lower platelet count and increase MPV; two additional P/LPVs increase MPV only (Fig.1). Analysis of 102 P/LPVs for AR-platelet disorders, showed that GP9:p.Asn61Ser (causal of Bernard-Soulier-Syndrome in homozygosity/compound heterozygosity), significantly reduces platelet count in carriers (-0.6 SD, P = 3x10-14, n=169). Paradoxically, platelet counts of carriers of one of three MPL variants (causal of Congenital-Amegakaryocytic-Thrombocytopenia (CAMT)) are significantly increased (Fig.2).

Conclusion(s): For the first time ever, we have accurately calculated effect sizes of P/LPVs deemed causal of platelet disorders; we observe platelet count/volume effect sizes have generally been overestimated. Our results demonstrate the clinical penetrance of P/LPVs causal of AR-platelet disorders. Unexpectedly, carrying a loss-of-function MPL variant, which in homozygosity/compound heterozygosity cause CAMT, increases platelet count.