Pierre Fontanillas’s research while affiliated with 23andMe and other places

The landscape of cancer treatment has been transformed by immune checkpoint inhibitors; however, the failure to benefit a large number of patients with cancer has underlined the need to identify promising targets for more effective interventions. In this study, we leverage 23andMe, Inc.’s large-scale human germline genetic and health database to uncover the previously unknown role of UL16-binding protein 6 (ULBP6), a high-affinity NK group 2D (NKG2D) ligand, in cancer and its promise as an immuno-oncology therapeutic target. We confirm ULBP6 expression in human tumors and demonstrate that soluble ULBP6 shed from tumors circumvents NKG2D activation provided by membrane-anchored NKG2D ligands to inhibit immune cell activation and tumor cell killing. Based on these findings, we developed 23ME-01473, a humanized Fc effector–enhanced antibody that binds to ULBP6 and its closely related family members, ULBP2 and ULBP5. 23ME-01473 effectively blocks soluble ULBP6-mediated immunosuppression to restore the NKG2D axis on NK and T cells to elicit tumor growth control. Moreover, the Fc effector–enhanced design of 23ME-01473 increases its binding affinity to fragment crystallizable gamma receptor IIIa, which, together with 23ME-01473’s binding to membrane-anchored ULBP6/2/5 on cancer cells, allows for augmented antibody-dependent cellular cytotoxicity induction, providing a second activation node for NK cells. Our studies demonstrate the therapeutic potential of an Fc effector–enhanced anti-ULBP6/2/5 antibody to reinvigorate NK cell and T-cell activation and cytotoxicity for the treatment of cancer. Significance This study emphasizes the utility of population-based genome-wide assessments for discovering naturally occurring genetic variants associated with lifetime risks for cancer or immune diseases as novel drug targets. We identify ULBP6 as a potential keystone member of the NKG2D pathway, which is important for antitumor immunity. Targeting ULBP6 may hold therapeutic promise for patients with cancer.

Background Impulsivity is a multidimensional trait associated with substance use disorders (SUDs), but the relationship between distinct impulsivity facets and stages of substance use involvement remains unclear. Methods We used genomic structural equation modeling and genome-wide association studies ( N = 79,729–903,147) to examine the latent genetic architecture of nine impulsivity traits and seven substance use (SU) and SUD traits. Results We found that the SU and SUD factors were strongly genetically inter-correlated ( r G =0.77) but their associations with impulsivity facets differed. Lack of premeditation, negative and positive urgency were equally positively genetically correlated with both the SU ( r G =.0.30–0.50) and SUD ( r G = 0.38–0.46) factors; sensation seeking was more strongly genetically correlated with the SU factor ( r G =0.27 versus r G =0.10); delay discounting was more strongly genetically correlated with the SUD factor ( r G =0.31 versus r G =0.21); and lack of perseverance was only weakly genetically correlated with the SU factor ( r G =0.10). After controlling for the genetic correlation between SU/SUD, we found that lack of premeditation was independently genetically associated with both the SU (β=0.42) and SUD factors (β=0.21); sensation seeking and positive urgency were independently genetically associated with the SU factor (β=0.48, β=0.33, respectively); and negative urgency and delay discounting were independently genetically associated with the SUD factor (β=0.33, β=0.36, respectively). Conclusions Our findings show that specific impulsivity facets confer risk for distinct stages of substance use involvement, with potential implications for SUDs prevention and treatment.

Hyposmia (decreased smell function) is a common early symptom of Parkinson’s disease (PD). The shared genetic architecture between hyposmia and PD is unknown. We leveraged genome-wide association study (GWAS) results for self-assessment of ‘ability to smell’ and PD diagnosis to determine shared genetic architecture between the two traits. Linkage disequilibrium score (LDSC) regression found that the sense of smell negatively correlated at a genome-wide level with PD. Local Analysis of [co]Variant Association (LAVA) found negative correlations in four genetic loci near GBA1 , ANAPC4 , SNCA , and MAPT , indicating shared genetic liability only within a subset of prominent PD risk genes. Using Mendelian randomization, we found evidence for a strong causal relationship between PD and liability towards poorer sense of smell, but weaker evidence for the reverse direction. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia.

This study aimed to test theoretical predictions over biological underpinnings of previously documented phenotypic correlations between human language-related and musical rhythm traits. Here, after identifying significant genetic correlations between rhythm, dyslexia and various language-related traits, we adapted multivariate methods to capture genetic signals common to genome-wide association studies of rhythm (N = 606,825) and dyslexia (N = 1,138,870). The results revealed 16 pleiotropic loci (P < 5 × 10-8) jointly associated with rhythm impairment and dyslexia, and intricate shared genetic and neurobiological architectures. The joint genetic signal was enriched for foetal and adult brain cell-specific regulatory regions, highlighting complex cellular composition in their shared underpinnings. Local genetic correlation with a key white matter tract (the left superior longitudinal fasciculus-I) substantiated hypotheses about auditory-motor connectivity as a genetically influenced, evolutionarily relevant neural endophenotype common to rhythm and language processing. Overall, we provide empirical evidence of multiple aspects of shared biology linking language and musical rhythm, contributing novel insight into the evolutionary relationships between human musicality and linguistic communication traits.

Importance: The lack of information on progression, phenoconversion, and risk of dementia in a large genotyped sample impedes reliable enrichment for early interventional trials in Parkinson's disease (PD). Objective: To investigate PD penetrance, risk, motor/non-motor phenotypes, and APOE allele effects in LRRK2 G2019S and GBA N370S carriers. Design: Observational longitudinal case-control self-report survey study. Setting: A US population-based study cohort enrolled in the 23andMe, Inc. and Fox Insight Genetic Substudy (FIGS) databases. Participants: The total cohort included 7,586,842 participants (n=35,163 PD; 27% of PD cases from FIGS); 8,791 LRRK2 G2019S carriers (565 with PD), 37,427 GBA N370S carriers (524 with PD), 244 dual carriers (37 with PD), and 7.5 million non-carriers (34,037 with PD). Exposure(s): LRRK2 G2019S, GBA N370S, APOE E2/E3/E4 alleles and PD polygenic risk scores (PRS). Main Outcome(s) and Measure(s): Cumulative incidence of PD was estimated using Kaplan-Meier and accelerated failure time models. Relative odds of developing motor and non-motor symptoms were calculated using logistic regression models according to genetic exposure. Impact of the APOE alleles was estimated in a dose-dependent analysis. Results: By the age of 80 years, the cumulative incidence of PD was 43% for dual carriers, 32% for LRRK2 G2019S carriers, 6% for GBA N370S carriers, and 3% for non-carriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. Motor symptoms were similar in LRRK2 G2019S, GBA N370S, and non-carriers with PD. GBA N370S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 G2019S the lowest. APOE E4 dosage was associated with greater odds of developing hallucinations and cognitive decline in addition to carrier status. Conclusions and Relevance: Our findings support the use of genetic screening--including LRRK2 G2019S, GBA N370S, APOE E4, and PRS--to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetic risk factors.

Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P < 5e⁻⁸) across 11 loci. Subgroup analyses revealed two of these were associated with early-onset (at age <50) and four with late-onset MG (at age ≥ 50). Imputation of human leukocyte antigen alleles revealed inverse effect sizes for late- and early-onset, suggesting a potential modulatory influence on the time of disease manifestation. We assessed the performance of polygenic risk scores for MG, which significantly predicted disease status in an independent target cohort, explaining 4.21% of the phenotypic variation (P = 5.12e⁻⁹). With this work, we aim to enhance our understanding of the genetic architecture of MG.

Background: Impulsivity is a multidimensional trait associated with substance use disorders (SUDs), but the relationship between distinct impulsivity facets and stages of substance use involvement remains unclear. Methods: We used genomic structural equation modeling and genome-wide association studies (N=79,729-903,147) based on individuals of European ancestry to examine the latent genetic architecture of impulsivity and substance use behaviors. We included GWAS data from nine impulsivity traits and seven substance use (SU) and SUD traits. Results: We found that the SU and SUD factors were strongly genetically inter-correlated (rG=0.77) but their associations with impulsivity factors differed. Lack of premeditation, negative and positive urgency were equally positively genetically correlated with both the SU (rG=.0.30-0.50) and SUD (rG=0.37-0.47) factors; sensation seeking was more strongly genetically correlated with the SU factor (rG=0.27 vs. rG=0.10); delay discounting was more strongly genetically correlated with the SUD factor (rG=0.32 vs. rG=0.21); and lack of perseverance was only weakly genetically correlated with the SU factor (rG=0.09). After controlling for the genetic correlation between SU/SUD, we found that lack of premeditation and positive urgency were independently genetically associated with both the SU (β=0.39, β=0.28, respectively) and SUD factors (β=0.28, β=0.19, respectively); sensation seeking and lack of perseverance were independently genetically associated with the SU factor (β=0.46, β=0.19, respectively); and negative urgency and delay discounting were independently genetically associated with the SUD factor (β=0.34, β=0.39, respectively). Conclusions: Our findings show that specific impulsivity facets confer risk for distinct stages of substance use involvement, with potential implications for SUDs prevention and treatment.

Background: Early detection of Parkinson's disease (PD), a neurodegenerative disease with central and peripheral nerve involvement, ensures timely treatment access. Microbes influence nervous system health and are altered in PD. Methods: We examined gut and mouth microbiomes from recently diagnosed patients in a geographically diverse, matched case-control, shotgun metagenomics study. Results: Here, we show greater alpha-diversity in 445 PD patients versus 221 controls. The microbial signature of PD includes overabundance of 16 OTUs, including Streptococcus mutans and Bifidobacterium dentium, and depletion of 28 OTUs. Machine learning models indicate that subspecies level oral microbiome abundances best distinguish PD with reasonably high accuracy (area under the curve: 0.758). Microbial networks are disrupted in cases, with reduced connectivity between short-chain fatty acid-producing bacteria the the gut. Importantly, microbiome diversity metrics are associated with non-motor autonomic symptom severity. Conclusions: Our results provide evidence that predictive oral PD microbiome signatures could possibly be used as biomarkers for the early detection of PD, particularly when there is peripheral nervous system involvement.

Adult height is a highly heritable polygenic trait with heritability attributable to thousands of independent variants. Large-scale studies have been able to detect genetic variants with contributions to height in the range of approximately 1.2 millimetre per allele copy on average. Non-additive genetic interactions may, in part, account for the difference between broad-sense and narrow-sense heritability estimates. However, prior studies have failed to identify variants with non-additive effects, possibly due to the lack of statistical power. Leveraging 3.6M individuals of European genetic ancestry in the 23andMe research cohort, we performed a genome-wide analysis study (GWAS) to select 1,063 independent common SNPs associated with height (p-value < 5e-8), and then screened for evidence of non-additive effects by analysing 564,453 models including a pairwise SNP-SNP interaction term. We identified 69 pairwise models with suggestive evidence of SNP-SNP interaction (p-value < 1e-4) and, for each SNP pair, we evaluated a fully saturated model including additive, dominant, and epistatic (additive-by-additive, additive-by-dominance and dominance-by-dominance) terms. We tested for the presence of epistatic interactions by comparing models with and without epistatic terms using a likelihood ratio test. Assuming a strict Bonferroni-corrected threshold of 8.9e-8 (0.05/564,453), we found no evidence of epistatic interactions (Likelihood ratio test (LRT) p-value < 9e-07 for all models). Our analysis rules out the existence of epistatic interactions between alleles of >1% frequency with effect sizes larger than 2.42mm. Our large-scale analysis provides further evidence of the minimal contribution of non-additivity in the genetic architecture of adult human height.