Selected Publications

There is increasing evidence that human leukocyte antigen (HLA) allelic variants play a role in the genetic predisposition to Parkinson disease (PD). In this regard, we have recently reported that the HLA-DRB1*04:01 allele, typified by residues Q/R-K/R-R-A-A at positions 70-74 in the HLA-DRβ1 chain in combination with valine at position 11 (11-V), confers moderate protective effects. In this study, we tested whether HLA-DRB1*04:01 can modulate PD pathology in vivo by employing a mouse model characterized by overexpression and aggregation of the PD-related protein alpha-synuclein, which was crossed with humanized mice expressing HLA-DRB1*04:01. Our results indicate that shared epitope-positive HLA alleles protect against alpha-synuclein pathology through increased microglial phagocytosis and inhibition of astrocyte reactivity.

The timing of the biological onset of multiple sclerosis (MS) is unclear. We used high-throughput discovery proteomics and samples from presymptomatic patients with MS and matched healthy controls to define the biological neurological onset and characterize the mechanisms involved. Remarkably, evidence of myelin injury was seen ~7 years before the symptomatic onset and preceded evidence of axonal injury by ~1 year. By contrast, astrocyte involvement became evident only at clinical onset. Proteomic network analysis identified a specific set of oligodendrocyte-associated proteins as the main drivers of myelin injury during the presymptomatic period, suggesting that myelin damage initiates the MS disease cascade and represents a highly relevant target for prevention or pre-symptomatic treatment.

Spinal cord (SC) atrophy correlates with and predicts the underlying progressive biology in active and non-active multiple sclerosis (MS), thereby providing a biomarker for clinical trials and patient management. Initiation of disease-modifying therapy (DMT) may be followed by early pronounced central nervous system (CNS) volume loss due to resolution of inflammation (pseudoatrophy) and confounding the interpretation of atrophy. In this study, we show that high-dose pulse glucocorticoid treatment administered at diagnosis effectively prevents white matter pseudoatrophy in the spinal cord of newly diagnosed MS patients, offering insights into early treatment strategies that may preserve spinal cord integrity during the initial phase of disease management.

Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment. Using a multi-center retrospective cohort analysis, we identify HLA-A*03:01 as a predictive genetic biomarker for glatiramer acetate treatment response in multiple sclerosis, demonstrating that HLA genotyping could inform personalized treatment selection in MS.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To refine the genetic map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 46 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

The impact of menopause on the brain is not well understood. Hormonal changes, including puberty and pregnancy, influence the onset and course of multiple sclerosis (MS). After menopause, a worsening of MS disease trajectory measured on the clinician-rated Expanded Disability Status Scale (EDSS) was reported in some, but not all, studies. Evaluating the association between menopause and more objective measures of CNS injury is needed. Using the UCSF MS-EPIC longitudinal cohort, we assessed the association between menopause and functional outcomes including brain MRI, retinal imaging, and MS-related biomarkers in women with MS, finding that menopausal status is associated with accelerated neurodegeneration and disability worsening that is partially independent of chronological age.

The extremely high levels of genetic polymorphism within the human major histocompatibility complex (MHC) limit the usefulness of reference-based alignment methods for sequence assembly. We incorporate a short-read, de novo assembly algorithm into a workflow for novel application to the MHC. MHConstructor is a containerized pipeline designed for high-throughput, haplotype-informed, reproducible assembly of both whole genome sequencing and target capture short-read data in large, population cohorts. To-date, no other self-contained tool exists for the generation of de novo MHC assemblies from short read data. MHConstructor facilitates wide-spread access to high quality, alignment-free MHC sequence analysis.

A fundamental endeavor of the International Histocompatibility and Immunogenetics Workshop (IHIW) was assembling a collection of DNA samples homozygous through the MHC genomic region. This collection proved invaluable for assay development in the histocompatibility and immunogenetics field, for generating the human reference genome, and furthered our understanding of MHC diversity. In this workshop component, we are collecting the next generation of MHC-homozygous samples, to expand, diversify and modernize this critical community resource. We asked laboratories worldwide to identify samples homozygous through all HLA class I and/or HLA class II genes, or through whole-genome SNP genotyping or sequencing. Through this effort, we have obtained samples from 537 individuals representing 294 distinct haplotypes.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination—prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury.

Multiple sclerosis patients would benefit from machine learning algorithms that integrate clinical, imaging and multimodal biomarkers to define the risk of disease activity. We have analysed a prospective multi-centric cohort of 322 MS patients and 98 healthy controls from four MS centres, collecting disability scales at baseline and 2 years later. Imaging data included brain MRI and optical coherence tomography, and omics included genotyping, cytomics and phosphoproteomic data from peripheral blood mononuclear cells. Predictors of clinical outcomes were searched using Random Forest algorithms. We found algorithms for predicting confirmed disability accumulation, no evidence of disease activity (NEDA), onset of immunotherapy and the escalation from low- to high-efficacy therapy with intermediate to high-accuracy.

The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls. We identified 132 differentially methylated regions (DMRs) within the MHC region associated with disease status. Integration of the MHC methylome with HLA genetic data indicates that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMR paired associations.

Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS; however, data on the association between NfL level and disability accumulation have been conflicting. This study documents the occurrence of NfL elevation in advance of clinical worsening—in CDW associated with relapses (CDW-R) and in CDW independent of relapses (CDW-NR)—providing evidence of a potential window of dynamic CNS pathology that precedes the diagnosis of confirmed disability worsening.

Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship and shared molecular factors between psoriasis and MS. We used logistic regression, trans-disease meta-analysis, and Mendelian randomization, using data from over 30 million patients and revealing more than 20 shared genetic loci outside the MHC including genes such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis has a significant causal effect on MS.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected. We conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of 3.7 years in homozygous carriers. We also identified significant heritability enrichment in CNS tissues. Mendelian randomization suggested a protective role for higher educational attainment. These findings suggest a key role for CNS resilience and neurocognitive reserve in determining outcome in MS.

Genome-wide association studies (GWAS) successfully identified multiple sclerosis (MS) susceptibility variants. Despite this progress, understanding the biological context of these associations remains challenging. We aimed to address this gap by integrating GWAS data with single-cell and bulk chromatin accessibility data and histone modification profiles from immune and nervous systems. MS-GWAS associations are significantly enriched in regulatory regions of microglia and peripheral immune cell subtypes, especially B cells and monocytes. Cell-specific polygenic risk scores demonstrated significant associations with risk and brain white matter volume, consistent with the known pathology and presumed targets of effective MS therapeutics.

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility. We developed polygenic risk scores (PRS) for MS and assessed associations with disease status and severity in cohorts of European descent, leveraging the largest GWAS dataset for MS to date (n = 41,505). Individuals in the top 10% of PRS were at more than 5-fold increased risk in UK Biobank and 15-fold higher risk in Kaiser Permanente Northern California. PRS inclusion in clinical risk models increased risk discrimination by 13–26%. We also show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort, indicating partial overlap between the genetics of susceptibility and end-organ tissue injury.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2,652 Latinx and Hispanic individuals as well as 2,435 Black and African American individuals. We identified several novel susceptibility alleles including HLA-B*53:01, and utilized differing linkage disequilibrium patterns to identify independent roles for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. A decrease in Native American ancestry was found in MS cases vs controls across the MHC, and HLA-DQB1*06:02 MS risk for European allele carriers is almost two times that for African allele carriers.

Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV reactivates and infects the brain. We hypothesized that patients may also have genetic susceptibility from rare deleterious genetic variants in immune-relevant genes. In a study of 152 cases, we validated 4 of 19 previously identified candidate PML risk variants in immune system genes: C8B, LY9, FCN2, and STXBP2. Carriers of any one of these variants are at high risk of PML when drug-exposed (P = 3.50E-06, OR = 8.7). For the first time, a PML genetic risk test can be implemented for screening patients taking PML-linked drugs.

ATXN1 encodes the polyglutamine protein ataxin-1, which we have demonstrated exerting an immunomodulatory function in the context of central nervous system (CNS) autoimmunity. In this study, we dissected the contribution of DNA methylation to the regulation of ATXN1 in multiple sclerosis (MS). We report that ATXN1 undergoes hypo-methylation at four distinct regions upon MS, exclusively in B cells. These differentially methylated sites overlap with other regulatory epigenetic marks and MS risk variants. Luciferase assays showed that the loss of methylation leads to an increase in ATXN1 expression. These findings provide biological insights into ataxin-1 regulation in the immune system and the molecular mechanisms underlying MS risk.

Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS with no evidence of disease activity or progression (NEDAP). Plasma NfL concentrations were 9.6% lower in samples collected during active treatment with clemastine (geometric mean 6.33 pg/mL) compared to placebo (7.00 pg/mL), suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.

The human leukocyte antigen (HLA) locus encodes a large group of proteins governing adaptive and innate immune responses. HLA class II proteins form α/β heterodimers on antigen-presenting cells (APCs), displaying exogenous antigens to CD4+ T lymphocytes. We have previously shown that a shorter HLA-DRA isoform (sHLA-DRA) lacking 25 amino acids binds to canonical HLA-DR2 heterodimers on the cell membrane. Using atomistic molecular dynamics simulations, we show that a loop region exposed only in the short isoform (residues R69 to G83) is responsible for binding to the outer domain of the HLA-DR2 peptide-binding site, and that sHLA-DRA allosterically modifies the peptide-binding pocket conformation.

A comprehensive review article examining two decades of progress in multiple sclerosis research, treatment development, and patient outcomes. No abstract available.

Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans, we studied the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive MS (SPMS). Patients who developed SPMS showed faster cord atrophy rates (−2.19%/yr) at least 4 years before conversion compared to matched RRMS patients (−0.88%/yr). Each 1% faster spinal cord atrophy rate was associated with 69% shorter time to silent progression and 53% shorter time to SPMS conversion. Silent progression and SPMS conversion are predominantly related to cervical cord atrophy, often present from earliest disease stages.

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). We conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation.

The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls who self-identified as African-American. We investigated the relationship between MS-susceptibility and the conserved extended haplotype (CEH) make-up of this cohort. Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans, whereas 9 (28%) occurred more frequently or exclusively in Europeans. European CEHs linked to MS-risk had similar impacts in African-Americans as in Europeans. By contrast, African CEHs had mixed MS-risks—for many, these CEHs were "protective"—providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.