Leveraging sex-genetic interactions to understand brain disorders: recent advances and current gaps.

It is established that there are sex differences in terms of prevalence, age of onset, clinical manifestations, and response to treatment for a variety of brain disorders, including neurodevelopmental, psychiatric, and neurodegenerative disorders. Cohorts of increasing sample sizes with diverse data types collected, including genetic, transcriptomic and/or phenotypic data, are providing the building blocks to permit analytical designs to test for sex-biased genetic variant-trait associations, and for sex-biased transcriptional regulation. Such molecular assessments can contribute to our understanding of the manifested phenotypic differences between the sexes for brain disorders, offering the future possibility of delivering personalized therapy for females and males. With the intention of raising the profile of this field as a research priority, this review aims to shed light on the importance of investigating sex-genetic interactions for brain disorders, focusing on two areas: (i) variant-trait associations and (ii) transcriptomics (i.e. gene expression, transcript usage and regulation). We specifically discuss recent advances in the field, current gaps and provide considerations for future studies.

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.

Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes.

There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, Df, might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present a genome-wide association study (GWAS) of 38,000 individuals with white British ancestry from the UK Biobank aimed to comprehensively study the genetic component of Df and analyse its relationship with CAD. We replicated 5 Df loci and found 4 additional loci with suggestive significance (P < 1e-05) to contribute to Df variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD's fatal outcomes. Fine-mapping of Df loci revealed Notch signalling regulatory variants supporting a shared mechanism with MI outcomes. We developed a predictive model for MI incident cases, recorded over a 10-year period following clinical and ophthalmic evaluation, combining clinical information, Df, and a CAD polygenic risk score. Internal cross-validation demonstrated a considerable improvement in the area under the curve (AUC) of our predictive model (AUC = 0.770 ± 0.001) when comparing with an established risk model, SCORE, (AUC = 0.741 ± 0.002) and extensions thereof leveraging the PRS (AUC = 0.728 ± 0.001). This evidences that Df provides risk information beyond demographic, lifestyle, and genetic risk factors. Our findings shed new light on the genetic basis of Df, unveiling a common control with MI, and highlighting the benefits of its application in individualised MI risk prediction.

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.

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.

A large Canadian cohort provides insights into the genetic architecture of human hair colour.

Hair colour is a polygenic phenotype that results from differences in the amount and ratio of melanins located in the hair bulb. Genome-wide association studies (GWAS) have identified many loci involved in the pigmentation pathway affecting hair colour. However, most of the associated loci overlap non-protein coding regions and many of the molecular mechanisms underlying pigmentation variation are still not understood. Here, we conduct GWAS meta-analyses of hair colour in a Canadian cohort of 12,741 individuals of European ancestry. By performing fine-mapping analyses we identify candidate causal variants in pigmentation loci associated with blonde, red and brown hair colour. Additionally, we observe colocalization of several GWAS hits with expression and methylation quantitative trait loci (QTLs) of cultured melanocytes. Finally, transcriptome-wide association studies (TWAS) further nominate the expression of EDNRB and CDK10 as significantly associated with hair colour. Our results provide insights on the mechanisms regulating pigmentation biology in humans.

Meta-analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations.

BACKGROUND: Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations. RESULTS: We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response. CONCLUSIONS: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.

Shades of complexity: New perspectives on the evolution and genetic architecture of human skin.

Like many highly variable human traits, more than a dozen genes are known to contribute to the full range of skin color. However, the historical bias in favor of genetic studies in European and European-derived populations has blinded us to the magnitude of pigmentation's complexity. As deliberate efforts are being made to better characterize diverse global populations and new sequencing technologies, better measurement tools, functional assessments, predictive modeling, and ancient DNA analyses become more widely accessible, we are beginning to appreciate how limited our understanding of the genetic bases of human skin color have been. Novel variants in genes not previously linked to pigmentation have been identified and evidence is mounting that there are hundreds more variants yet to be found. Even for genes that have been exhaustively characterized in European populations like MC1R, OCA2, and SLC24A5, research in previously understudied groups is leading to a new appreciation of the degree to which genetic diversity, epistatic interactions, pleiotropy, admixture, global and local adaptation, and cultural practices operate in population-specific ways to shape the genetic architecture of skin color. Furthermore, we are coming to terms with how factors like tanning response and barrier function may also have influenced selection on skin throughout human history. By examining how our knowledge of pigmentation genetics has shifted in the last decade, we can better appreciate how far we have come in understanding human diversity and the still long road ahead for understanding many complex human traits.

Whole mitochondrial genome capture from faecal samples and museum-preserved specimens.

Population-scale molecular studies of endangered and cryptic species are often limited by access to high-quality samples. The use of noninvasively collected samples or museum-preserved specimens reduces the pressure on modern populations by removing the need to capture and handle live animals. However, endogenous DNA content in such samples is low, making shotgun sequencing a financially prohibitive approach. Here, we apply a target enrichment method to retrieve mitochondrial genomes from 65 museum specimens and 56 noninvasively collected faecal samples of two endangered great ape species, Grauer's gorilla and the eastern chimpanzee. We show that the applied method is suitable for a wide range of sample types that differ in endogenous DNA content, increasing the proportion of target reads to over 300-fold. By systematically evaluating biases introduced during target enrichment of pooled museum samples, we show that capture is less efficient for fragments shorter or longer than the baits, that the proportion of human contaminating reads increases postcapture although capture efficiency is lower for human compared to gorilla fragments with a gorilla-generated bait, and that the rate of jumping PCR is considerable, but can be controlled for with a double-barcoding approach. We succeed in capturing complete mitochondrial genomes from faecal samples, but observe reduced capture efficiency as sequence divergence increases between the bait and target species. As previously shown for museum specimens, we demonstrate here that mitochondrial genome capture from field-collected faecal samples is a robust and reliable approach for population-wide studies of nonmodel organisms.