Regional genetic correlations highlight relationships between neurodegenerative disease loci and the immune system

Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are devastating complex diseases resulting in physical and psychological burdens on patients and their families. There have been important efforts to understand their genetic basis leading to the identification of disease risk-associated loci involved in several molecular mechanisms, including immune-related pathways. Regional, in contrast to genome-wide, genetic correlations between pairs of immune and neurodegenerative traits have not been comprehensively explored, but could uncover additional immune-mediated risk-associated loci. Here, we systematically assess the role of the immune system in five neurodegenerative diseases by estimating regional genetic correlations between these diseases and immune-cell-derived single-cell expression quantitative trait loci (sc-eQTLs). We also investigate correlations between diseases and protein levels. We observe significant (FDR < 0.01) correlations between sc-eQTLs and neurodegenerative diseases across 151 unique genes, spanning both the innate and adaptive immune systems, across most diseases tested. With Parkinson’s, for instance, RAB7L1 in CD4+ naïve T cells is positively correlated and KANSL1-AS1 is negatively correlated across all adaptive immune cell types. Follow-up colocalization highlight candidate causal risk genes. The outcomes of this study will improve our understanding of the immune component of neurodegeneration, which can warrant repurposing of existing immunotherapies to slow disease progression

Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases

Genetic correlation ([Formula: see text]) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global [Formula: see text] analyses show minimal [Formula: see text] among neurodegenerative and neuropsychiatric diseases. Importantly, local [Formula: see text] s can exist in the absence of global relationships. To investigate this possibility, we applied LAVA, a tool for local [Formula: see text] analysis, to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer's disease, Lewy body dementia and Parkinson's disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several local [Formula: see text] s missed in global analyses, including between (i) all 3 neurodegenerative diseases and schizophrenia and (ii) Alzheimer's and Parkinson's disease. For those local [Formula: see text] s identified in genomic regions containing disease-implicated genes, such as SNCA, CLU and APOE, incorporation of expression quantitative trait loci identified genes that may drive genetic overlaps between diseases. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes. These findings imply sharing of pathogenic processes and the potential existence of common therapeutic targets

The Genetic Architecture of Pigmentation Traits in Modern Human Populations

Pigmentation traits, here defined as hair, eye and constitutive skin pigmentation are some the most variable phenotypes among human populations. They have a complex genetic basis, in which interactions among genes and pleiotropy are common. Several genes involved in the pigmentation pathway have been described across mammalian species, which explain a significant proportion of the normal pigmentation variation in humans. However, the full understanding of the genetic architecture of pigmentation in human populations has not yet been achieved. Major effect genes are known to explain a relatively high proportion of the variance for each pigmentation trait at a population-basis level, but a substantial number of genetic loci modulating pigmentation in several populations have small effects and remain unknown. The objective of my thesis was to contribute to and improve the state of knowledge of the genetic architecture of pigmentation traits in modern humans. To achieve this, I have taken advantage of novel approaches at different stages of the research program, such as the use of large sample sizes and different cohorts, the application of diverse statistical approaches, and the use of genomic and epigenomic databases and computational advances to follow-up putative causal loci. I have identified a complex genetic architecture across known pigmentation regions such as TYR and OCA2, in which a combination of missense and non-coding SNPs are independently associated with pigmentation traits. These associations seem to vary among populations and among pigmentation traits to certain extent, as evidenced by fine-mapping and genetic correlations in a Canadian cohort of European ancestry. Finally, I explored the putative regulatory role of pigmentation loci. I have identified shared causal signals between hair or eye colour and quantitative trait loci (i.e. methylation and expression), and I have identified significant associations between hair or eye colour and the expression of pigmentation genes such as OCA2 and SLC24A4. Overall, my research has nominated several candidate causal variants across loci, and has provided insights to further explore the biological role of these SNPs in human pigmentation.Ph.D

Investigating the genetic architecture of eye colour in a Canadian cohort

Eye color is highly variable in populations with European ancestry, ranging from low to high quantities of melanin in the iris. Polymorphisms in the HERC2/OCA2 locus have the largest effect on eye color in these populations, although other genomic regions also influence eye color. We performed genome-wide association studies of eye color in a Canadian cohort of European ancestry (N = 5,641) and investigated candidate causal variants. We uncovered several candidate causal signals in the HERC2/OCA2 region, whereas other loci likely harbor a single causal signal. We observed colocalization of eye color signals with the expression or methylation profiles of cultured primary melanocytes. Genetic correlations of eye and hair color suggest high genome-wide pleiotropy, but locus-level differences in the genetic architecture of both traits. Overall, we provide a better picture of the polymorphisms underpinning eye color variation, which may be a consequence of specific molecular processes in the iris melanocytes