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bioRxiv2026

Predominantly genetic determination and stable transmission of DNA methylation in an avian hybrid zone

The reshuffling of divergent genomes upon hybridization may disrupt co-evolved regulatory systems and contribute to epigenetic instability and, ultimately, reproductive isolation. While the genetic consequences of hybridization are well documented, insights into the consequences of hybridization for DNA methylation are currently limited. To obtain insights into the regulation of methylation and its transmission under hybridization, we here investigated genome-wide methylation in a natural hybrid zone of songbirds (wheatears of the Oenanthe hispanica complex) by integrating nearly 100 methylomes with population genomic data. Across 436,762 CpG sites, the population structure of methylation closely mirrors genetic population structure. Methylation quantitative trait locus analyses identify widespread associations of genetic with methylation variation, predominantly in trans, consistent with a regulatory architecture in which the genetic background determines methylation variation. Between species, methylation divergence is limited, with only 0.31% of CpGs differentially methylated. While at the level of chromosomes methylation divergence strongly correlates with genetic differentiation, the extent to which differentially methylated loci coincide with high genetic differentiation differs among chromosomes. A close-to-absent methylation divergence from promoters and coding regions indicates conservation of core regulatory architectures. Finally, CpGs with highest methylation divergence exhibit predominantly additive or dominant transition patterns in hybrids. In contrast, transgressive methylation is exceedingly rare, and we find no evidence for widespread hybrid-induced demethylation. Or results corroborate that DNA methylation primarily reflects underlying genetic variation in birds and remains robust to genome reshuffling, and at least for wheatears suggest a limited role for methylation divergence in hybrid dysfunction and reproductive isolation.

evolutionary biology↗

bioRxiv2026

Beyond Fixation: Persistent Genetic Variation Under Intense Selection

Understanding how and why genetic variation is maintained under sustained selection remains a central question in evolutionary genetics. Experimental evolution shows that adaptation in sexually reproducing populations is often highly polygenic, proceeding through coordinated, genome-wide allele frequency shifts from standing variation rather than classic hard sweeps. Recent explanations emphasize highly polygenic architectures, optimizing-selection, and genetic redundancy, which can slow fixation by distributing selection across many loci during adaptation. However, observations from long-term selection experiments reveal a pattern these frameworks do not fully explain: substantial genetic variation persists after hundreds of generations of intense directional selection in constant environments. Here, we use long-term experimental evolution in Drosophila melanogaster to test whether balancing-selection actively maintains genetic variation under strong life-history selection and preserves evolutionary reversibility. Longstanding populations selected for accelerated or delayed reproduction were shifted to the opposing regime, imposing age-structured fitness trade-offs. Notably, selection for early reproduction is associated with substantial loss of genetic variation, providing a stringent test of whether standing variation is truly depleted. Following reciprocal shifts, populations showed rapid phenotypic convergence toward the target regime. At the genomic level, allele-frequency trajectories were strongly antiparallel and highly repeatable across replicates, revealing coordinated polygenic responses. Relaxing long-standing early-life selection produced a pronounced rebound in genome-wide heterozygosity. Deep sequencing uncovered ultra-rare alleles at sites appearing fixed under standard coverage, indicating low-frequency functional variation persists below detection thresholds. These results suggest that substantial genetic variation can persist under intense directional selection and be rapidly redeployed when selection reverses, consistent with widespread balancing-selection.

evolutionary biology↗

bioRxiv2026

The relationship between genomic variation and genetic load: insights from small island populations

Small populations face high extinction risks. This can be explained by several non-genetic and genetic factors, the latter including the loss of genetic diversity and evolutionary potential, as well as the accumulation of harmful mutations (genetic load). Using whole-genome data from island populations with different effective sizes, we estimated genetic variation and load and explored the relationship between these quantities. An extremely small population of the Aeolian wall lizard, Podarcis raffonei, likely isolated for tens of thousands of years, shows the lowest genome-wide heterozygosity observed in wild eukaryotes (one polymorphic site every 300 kb on average). Despite this, its realized genetic load is comparable to that observed in another larger and more genetically variable population. Both populations have lower variation and higher load than the much more abundant sister species, the Sicilian wall lizard. These observations are consistent with the hypothesis that populations experiencing severe bottlenecks may persist for extended periods with extremely low genomic variation, provided that their burden of deleterious mutations remains within tolerable bounds.

genomics↗

bioRxiv2026

Climate Gradients and Habitat Discontinuity Structure Genetic Variation in a Spring-Specialist Plant

Background and AimsGroundwater-dependent ecosystems support disproportionate biodiversity in arid regions, yet the population genetics of spring-specialist plants remains poorly understood. Here, we present the first species-wide genetic dataset for crimson monkeyflower ( Mimulus verbenaceus, Phrymaceae), a spring-specialist plant distributed in seeps, springs, and associated riparian areas across desert regions of North America. MethodsUsing genome-wide reduced representation sequencing data consisting of 10,760 SNPs from 175 individuals across 17 populations, we characterized the patterns of genetic diversity using FST and Neis D. Population structure was assessed using ADMIXTURE and PCA. We examined the contributions of climate to range-wide genetic variation in crimson monkeyflower using redundancy analysis. Key ResultsPatterns of genetic differentiation were more consistent with those of spring-specialist animal taxa than those of upland plants or generalist riparian plants. We found strong population structure at both broad regional scales and at fine local scales. While riparian connectivity influenced local patterns of diversity, adaptation to local climatic variation was more influential at regional scales, with temperature, relative humidity, and a monsoon-driven climate gradient structuring genetic differentiation. ConclusionsOur findings highlight the distinctive influence of isolated perennial groundwater sources, as well as adaptation to climate, in shaping genetic variation in this spring-specialist plant. These findings suggest that spring-specialist plants deserve special consideration in ecological theory, management, and conservation.

evolutionary biology↗

bioRxiv2026

Population-scale transcriptomics reveals host genetic control of phyllosphere fungal communities

The composition of plant-associated microbial communities plays a central role in host health and agricultural productivity, yet the genetic basis of plant-fungal interactions in the phyllosphere remains poorly understood. Progress has been limited in part by technical challenges in profiling low-abundance fungal communities and linking their variation to host genetics. Here we show that standard polyA-enriched RNA sequencing of plant leaf tissue, without targeted microbial enrichment, captures sufficient fungal transcripts to enable quantitative profiling of metabolically active mycobiomes at scale. Although fungal transcripts represented only 0.03-0.4% of classified reads in standard polyA-enriched leaf RNA-seq datasets, this still yielded >79 million fungal reads across 2,194 field-collected samples (median = 5,260-59,746 reads per sample), enabling robust quantification of several hundred fungal taxa. Leveraging these data, we perform genome-wide association and transcriptome-wide association analyses of fungal relative abundance and identify widespread host genetic control of phyllosphere fungal communities. We detect extensive and biologically structured associations between host genetic variation, gene expression, and fungal abundance across all three crops, including numerous loci with multi-taxon effects and strong colocalization between GWAS and expression quantitative trait loci. Network and module-level analyses further reveal coordinated host transcriptional programs linked to fungal community variation, while integration of orthologous gene sets indicates partial conservation but substantial species specificity in underlying genetic architecture. Together, these results demonstrate that standard RNA-seq datasets contain sufficient ecological signal to enable high-resolution microbiome genetic mapping and reveal that host genetic control of phyllosphere fungal communities is more pervasive than previously appreciated. This framework provides a scalable approach for reusing existing transcriptomic datasets to study plant-microbe interactions across diverse species and environments.

genomics↗

bioRxiv2026

Contrasting effects of forest fragmentation on the genetics and microbiomes of an endangered arboreal primate

Landscape fragmentation, one of the leading drivers of biodiversity loss, can reshape both the genetics and microbiomes of wild populations. Although fragmentation is generally expected to limit gene flow and erode genetic diversity, and to disrupt host-associated microbial communities, these responses arise via different pathways and may therefore diverge within the same population. To understand how fragmentation simultaneously shapes population genetics and gut microbiomes, we analyzed fecal-derived host genomic and microbiome data from endangered, arboreal black howler monkeys (Alouatta pigra) across a fragmentation gradient. We then integrated these data with measures of ecological connectivity, habitat quality, and demography to identify the drivers of genetic and microbiome variation and structure. Multivariate analyses indicated that genetic patterns were shaped by both connectivity and habitat quality, whereas microbiome variation was driven mainly by habitat quality. Contrary to expectations under reduced realized connectivity with increasing isolation, monkeys showed the strongest gene flow signal in the most fragmented region, and higher genetic diversity and lower inbreeding than monkeys in continuous forest. Relatedness and isolation-by-distance patterns suggested that fragmentation has sex-specific effects on movement, disrupting the usual pattern of short-range male dispersal in the most fragmented region. Gut microbiomes, however, showed predicted negative responses to fragmentation: individuals in highly fragmented habitat had lower microbial diversity and compositional shifts consistent with lower-quality diets and increased exposure to disturbed environments. These results show contrasting biological responses to fragmentation within a single population, with genetic patterns likely resulting from compensatory behavioral flexibility and microbiome patterns reflecting local habitat degradation. Our findings underscore the need for conservation assessments that integrate multiple dimensions of population health rather than relying on any single indicator of fragmentation impact.

ecology↗

bioRxiv2026

Intraspecific morphological variability of the invasive mosquito Aedes koreicus in Europe: genetic characterisation and population-level insights

BackgroundThe invasive mosquito Aedes koreicus has established populations in several European countries during the past decade, raising increasing public health concerns due to its potential role as a vector of pathogens. While species identification is primarily based on morphological characters, Ae. koreicus exhibits distinct morphological variants originating from mainland Korea and Jeju Island, which complicates surveillance and may lead to misidentification, particularly in regions where closely related species co-occur. To date, the genetic basis and population-level relevance of these morphological forms in Europe remain poorly understood. MethodsWe investigated the co-occurrence of two morphological forms of Ae. koreicus in Hungary, representing the first confirmed European location where both forms were detected sympatrically and even within the same breeding sites. Adult mosquitoes were morphologically characterised using diagnostic traits, and individuals representing both morphotypes were subjected to comprehensive genetic analyses. We sequenced multiple mitochondrial markers (COX1, COX2, COX3, ATP6, ND1, ND3) and the nuclear ITS2 region using Oxford Nanopore long-read sequencing. Phylogenetic reconstructions and haplotype network analyses were applied to assess genetic differentiation between morphotypes and to compare them with Aedes japonicus as a closely related reference species. ResultsAcross all analysed mitochondrial and nuclear markers, no genetic differentiation was detected between specimens identified as the "mainland" or "Jeju-do" morphological forms of Ae. koreicus. Phylogenetic and haplotype network analyses consistently grouped individuals independently of their morphotype, indicating a shared genetic background at the population level. In contrast, Ae. japonicus formed a clearly distinct genetic lineage, confirming the robustness of the applied markers for interspecific discrimination. ConclusionsOur results demonstrate that the observed morphological variability in Ae. koreicus populations are not underpinned by detectable genetic differentiation using commonly applied mitochondrial and genomic markers. These findings highlight the limitations of using morphology alone to infer population origin or structure and emphasise the need for heightened awareness of intraspecific variability in routine surveillance. Accurate morphological identification remains critical, particularly in citizen science-based monitoring programmes and AI-based automatization platforms, such as Mosquito Alert, to avoid confusion with morphologically similar invasive species. Further studies integrating genomic and ecological approaches are required to elucidate the mechanisms underlying morphological variability in this emerging vector species.

zoology↗

bioRxiv2026

Haplotype-based insights into the genetic architecture of net blotch resistance in barley

Net blotch, caused by Pyrenophora teres, is a major constraint to barley production worldwide and occurs as two epidemiologically distinct forms: net form net blotch (NFNB) and spot form net blotch (SFNB). Although numerous resistance loci have been reported in recent years, their genetic relationship remains poorly understood, and the effective deployment of resistance is constrained by the complex genetic architecture of net blotch resistance. In this study, we used a haplotype-based mapping approach to dissect the genetic basis of resistance to NFNB and SFNB in a diverse panel of 950 barley accessions from the Australian Grains Genebank (AGG). Disease responses were evaluated across 13 experiments, and a total of 40 quantitative trait loci (QTL) were identified, including 26 associated with NFNB, 29 with SFNB, and 15 common for both diseases. Most loci co-localized with previously reported QTL, while six putative novel haploblocks highlighted untapped genetic diversity within the AGG collection. Correlation analyses across phenotypic, genetic and haploblock levels revealed a partial but incomplete overlap in resistance mechanisms between NFNB and SFNB. Among the 4,497 haploblocks, approximately 60% of them showed positive local genetic correlations between the two diseases, suggesting shared genomic contributions to resistance. Haplotype composition analysis further identified a resistant haplotype group, mainly comprising accessions of Asian origin, that exhibited high levels of resistance to both forms of net blotch. Through in silico haplotype stacking, we demonstrated the cumulative genetic potential achievable by combining favourable haplotypes. When the breeding objective was to improve resistance to both NFNB and SFNB, dual-disease stacking strategies outperformed single-disease approaches, highlighting the value of prioritising haplotypes with positive pleiotropic effects. Overall, this study provides a comprehensive haplotype-level framework for understanding net blotch resistance and delivers practical insights for breeding barley cultivars with durable and broad-spectrum resistance to both NFNB and SFNB.

plant biology↗

bioRxiv2026

What shapes intraspecific genetic diversity in amphibians and reptiles? A comparative macrogenetic study across six biogeographic regions

Aim: Given that much of Earth's biodiversity is contained within species, inferring intraspecific genetic diversity and identifying its ecological correlates is essential for understanding evolutionary processes and informing conservation. Here, we investigate broad-scale variation in species-level mitochondrial genetic diversity and evaluate the relative importance of alternative ecological hypotheses proposed to explain it. Location: Brazilian Atlantic Forest, Iberian Peninsula, northwestern Africa, Arabian Peninsula, Madagascar and Australian Monsoonal Tropics. Taxon: Amphibians and reptiles Methods: We assembled a comprehensive dataset by integrating and manually curating mitochondrial sequences, occurrence records, environmental data and species traits from multiple open-access sources. We used multiple mitochondrial genes to estimate mean nucleotide diversity for each study species and quantified regional variation in genetic diversity. We then used random forests models to evaluate the relative importance of selected variables representing hypotheses related to water-energy availability, topography, historical climatic stability, land-cover characteristics, species geographic characteristics, life-history traits, evolutionary history and conservation status. Results: The final dataset comprised 247 amphibians and 295 reptiles, for which 43 and 52 explanatory variables were evaluated, respectively. Overall, the strongest support was found for hypotheses related to life-history traits, topographic heterogeneity and water-energy availability. In amphibians, higher genetic diversity was associated with smaller body size and greater environmental heterogeneity, particularly broader elevational and precipitation gradients. In reptiles, genetic diversity was primarily associated with life-history traits, with species of smaller body size and lower reproductive output exhibiting higher diversity. Long-term climatic stability showed comparatively little explanatory power for both taxa. Main conclusions: Our comprehensive study demonstrates that integrating extensive manual data curation with comparative macrogenetic analyses provides a robust framework for identifying broad-scale ecological correlates of mitochondrial genetic diversity. These findings improve our understanding of the factors associated with contemporary patterns of genetic diversity and provide a foundation for future conservation assessments in data-limited systems.

evolutionary biology↗

bioRxiv2026

Seascape genomics reveals shared spatial genetic structure in three co-occurring sea snakes

Marine species with broad distributions often exhibit complex patterns of genetic connectivity, shaped by historical and contemporary processes. Understanding these patterns is critical for conserving taxa threatened by ongoing and future environmental change. Here, we use reduced-representation and whole-genome sequencing to investigate population genetic patterns in three co-occurring sea snake species (Hydrophis stokesii, Hydrophis major, and Aipysurus laevis) across northern Australia and New Caledonia. Broadscale analyses revealed major genetic breaks across all species between: (1) Australia and New Caledonia, (2) northwestern and northeastern Australia, and (3) the offshore Timor Sea reefs and adjacent northwestern continental shelf of Australia. More subtle genetic differentiation was observed between Shark Bay in Western Australia and northern localities. All species showed relatively large effective population sizes and broadscale connectivity across ~1,300 km of Australia's northwestern continental shelf. This likely reflects substantial historical range expansion over late Quaternary timescales, which may have contributed to the observed genetic connectivity across the region. However, subtle patterns of isolation by distance emphasised the contribution of species-specific traits in shaping connectivity. The isolated offshore reef populations are genetically distinct and potentially threatened by environmental change. Disjunct populations in Shark Bay and the Timor Sea maintain similar levels of genetic diversity to the extensive continental shelf populations, while New Caledonian populations exhibit reduced diversity. Our results support the delineation of spatial units for sea snake conservation based on shared phylogeographic structure, while also finding important population- and species-specific differences in connectivity at finer spatial and temporal scales.

genomics↗

bioRxiv2026

Historical and Contemporary Management of Genetic Diversity in French Local Horse Breeds: Insights from Genomic Data

The phenotypic and genetic diversity of horses worldwide today likely resulted from two main events: (i) domestication and, afterwards, (ii) breed creation. While many studies discuss the origin and domestication of horses, very few focus on the second important event, which has largely shaped the genetic architecture of horses at present. This study exhaustively examined all 18 local horse breeds from France, all of which are endangered by small census sizes, making them prone to suffer from genetic drift, loss of diversity, and inbreeding depression. While pedigrees are available, they are often incomplete or error-prone. Thus, we used molecular markers to reconstruct the history of French local breeds and to monitor the evolution of genetic diversity and its link to management practices. The study was based on 976 animals (approx. 50 per breed), spanning two time periods corresponding to the change in management from public stud farms to privatization. The samples were genotyped using a 10K SNP array dedicated to genetic resources characterization. French local horses can be classified not only phenotypically but also genetically into two categories: the light 'territory' breeds and heavier 'draft' breeds, with regular gene flow observed between the two groups that are linked to historical records. The evolution of kinship and inbreeding over the two time periods exhibited distinct patterns between the cohorts and across the breeds, reflecting various consequences of different management practices. To conclude, this study was the first to exhaustively depict the evolution of French local horses, while it also demonstrated the usefulness of genomic data in monitoring genetic diversity and evaluating the effectiveness of management programs.

genomics↗

bioRxiv2018

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

bioRxiv2019

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 60% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38. Author SummaryWhile it is known that chronic obstructive pulmonary disease (COPD) is caused in part by genetic factors, few studies have identified specific causative genes. Genetic variants that alter the expression levels of genes have explained part of the genetic component of COPD, however, there are additional genetic variants with unknown function. In some genes the protein coding sequence can be altered by a mechanism known as RNA splicing. We hypothesized that some genetic variants that are associated with risk of COPD contribute to the disease by altering RNA splicing. In this study, we identified genetic variants that are associated both with COPD risk and RNA splicing. In particular, we found that a COPD associated variant of previously unknown function may contribute to the inclusion of a new exon in the FBXO38 gene. These finding are significant because they indicate that analysis of RNA splicing can help identify genes that contribute to disease.

genetics↗

bioRxiv2014

Genetic dissection of MAPK-mediated complex traits across S. cerevisiae

Signaling pathways enable cells to sense and respond to their environment. Many cellular signaling strategies are conserved from fungi to humans, yet their activity and phenotypic consequences can vary extensively among individuals within a species. A systematic assessment of the impact of naturally occurring genetic variation on signaling pathways remains to be conducted. In S. cerevisiae, both response and resistance to stressors that activate signaling pathways differ between diverse isolates. Here, we present a quantitative trait locus (QTL) mapping approach that enables us to identify genetic variants underlying such phenotypic differences across the genetic and phenotypic diversity of S. cerevisiae. Using a Round-robin cross between twelve diverse strains, we determined the genetic architectures of phenotypes critically dependent on MAPK signaling cascades. Genetic variants identified fell within MAPK signaling networks themselves as well as other interconnected signaling pathways, illustrating how genetic variation can shape the phenotypic output of highly conserved signaling cascades.

Genetics↗

bioRxiv2015

Inference and analysis of population structure using genetic data and network theory

Clustering individuals to subpopulations based on genetic data has become commonplace in many genetic studies. Inference of population structure is most often done by applying model-based approaches, aided by visualization using distance-based approaches such as multidimensional scaling. While existing distance-based approaches suffer from lack of statistical rigor, model-based approaches entail assumptions of prior conditions such as that the subpopulations are at Hardy-Weinberg equilibria. Here we present a distance-based approach for inference of population structure using genetic data by defining population structure using network theory terminology and methods. A network is constructed from a pairwise genetic-similarity matrix of all sampled individuals. The community partition, a partition of a network to dense subgraphs, is equated with population structure, a partition of the population to genetically related groups. Community detection algorithms are used to partition the network into communities, interpreted as a partition of the population to subpopulations. The statistical significance of the structure can be estimated by using permutation tests to evaluate the significance of the partitions modularity, a network theory measure indicating the quality of community partitions. In order to further characterize population structure, a new measure of the Strength of Association (SA) for an individual to its assigned community is presented. The Strength of Association Distribution (SAD) of the communities is analyzed to provide additional population structure characteristics, such as the relative amount of gene flow experienced by the different subpopulations and identification of hybrid individuals. Human genetic data and simulations are used to demonstrate the applicability of the analyses. The approach presented here provides a novel, computationally efficient, model-free method for inference of population structure which does not entail assumption of prior conditions. The method is implemented in the software NetStruct, available at https://github.com/GiliG/NetStruct.

Genetics↗

bioRxiv2015

Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause, and impact reproductive health: a UK Biobank study

Study question: How does a genetic variant altering follicle stimulating hormone (FSH) levels, which we identified as associated with length of menstrual cycle, more widely impact reproductive health?\n\nSummary answer: The T allele of the FSHB promoter polymorphism (rs10835638) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis.\n\nWhat is known already: The FSHB promoter polymorphism (rs10835638) affects levels of FSHB transcription and, as a result, levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS).\n\nStudy design, size, duration: We conducted a genetic association study using cross-sectional data from the UK Biobank.\n\nParticipants/materials, setting, methods: We included white British individuals aged 40-69 years in 2006-2010, included in the May 2015 release of genetic data from UK Biobank. We conducted a genome-wide association study (GWAS) in 9,534 individuals to identify genetic variants associated with length of menstrual cycle. We tested the FSH lowering T allele of the FSHB promoter polymorphism (rs10835638) for associations with 29 reproductive phenotypes in up to 63,350 individuals.\n\nMain results and the role of chance: In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P<5x10-8). The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638G>T; MAF 0.16) was associated with longer menstrual cycles (0.16 s.d. (approx. 1 day) per minor allele; 95% CI 0.12-0.20; P=6x10-16), later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P=5.7x10-3), greater female nulliparity (OR=1.06; 95% CI 1.02-1.11; P=4.8x10-3) and lower risk of endometriosis (OR=0.79; 95% CI 0.69-0.90; P=4.1x10-4). The FSH-lowering T allele was not associated more generally with other reproductive illnesses or conditions and we did not replicate associations with male infertility or PCOS.\n\nLimitations, reasons for caution: The data included might be affected by recall bias. Women with a cycle length recorded were aged over 40 and were approaching menopause, however we did not find evidence that this affected the results. Many of the illnesses had relatively small sample sizes and so we may have been under-powered to detect an effect.\n\nWider implications of the findings: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS.

Genetics↗

bioRxiv2016

Genetic heterogeneity in autism: from single gene to a pathway perspective

AbstractThe extreme genetic heterogeneity of autism spectrum disorder (ASD) represents a major challenge. Recent advances in genetic screening and systems biology approaches have extended our knowledge of the genetic etiology of ASD. In this review, we discuss the paradigm shift from a single gene causation model to pathway perturbation model as a guide to better understand the pathophysiology of ASD. We discuss recent genetic findings obtained through next-generation sequencing (NGS) and examine various integrative analyses using systems biology and complex networks approaches that identify convergent patterns of genetic elements associated with ASD. This review provides a summary of the genetic findings of family-based genome screening studies.

Genetics↗

bioRxiv2016

Mortality Selection in a Genetic Sample and Implications for Association Studies

Mortality selection is a general concern in the social and health sciences. Recently, existing health and social science cohorts have begun to collect genomic data. Causes of selection into a genomic dataset can influence results from genomic analyses. Selective non-participation, which is specific to a particular study and its participants, has received attention in the literature. But mortality selection--the very general phenomenon that genomic data collected at a particular age represents selective participation by only the subset of birth cohort members who have survived to the time of data collection--has been largely ignored. Here we test the hypothesis that such mortality selection may significantly alter estimates in polygenetic association studies of both health and non-health traits. We demonstrate mortality selection into genome-wide SNP data collection at older ages using the U.S.-based Health and Retirement Study (HRS). We then model the selection process. Finally, we test whether mortality selection alters estimates from genetic association studies. We find evidence for mortality selection. Healthier and more socioeconomically advantaged individuals are more likely to survive to be eligible to participate in the genetic sample of the HRS. Mortality selection leads to modest drift in estimating time-varying genetic effects, a drift that is enhanced when estimates are produced from data that has additional mortality selection. There is no general solution for correcting for mortality selection in a birth cohort prior to entry into a longitudinal study. We illustrate how genetic association studies using HRS data can adjust for mortality selection from study entry to time of genetic data collection by including probability weights that account for mortality selection. Mortality selection should be investigated more broadly in genetically-informed samples from other cohort studies.

Genetics↗