How structural variants shape avian phenotypes: Lessons from model systems.

Despite receiving significant recent attention, the relevance of structural variation (SV) in driving phenotypic diversity remains understudied, although recent advances in long-read sequencing, bioinformatics and pangenomic approaches have enhanced SV detection. We review the role of SVs in shaping phenotypes in avian model systems, and identify some general patterns in SV type, length and their associated traits. We found that most of the avian SVs so far identified are short indels in chickens, which are frequently associated with changes in body weight and plumage colouration. Overall, we found that relatively short SVs are more frequently detected, likely due to a combination of their prevalence compared to large SVs, and a detection bias, stemming primarily from the widespread use of short-read sequencing and associated analytical methods. SVs most commonly involve non-coding regions, especially introns, and when patterns of inheritance were reported, SVs associated primarily with dominant discrete traits. We summarise several examples of phenotypic convergence across different species, mediated by different SVs in the same or different genes and different types of changes in the same gene that can lead to various phenotypes. Complex rearrangements and supergenes, which can simultaneously affect and link several genes, tend to have pleiotropic phenotypic effects. Additionally, SVs commonly co-occur with single-nucleotide polymorphisms, highlighting the need to consider all types of genetic changes to understand the basis of phenotypic traits. We end by summarising expectations for when long-read technologies become commonly implemented in non-model birds, likely leading to an increase in SV discovery and characterisation. The growing interest in this subject suggests an increase in our understanding of the phenotypic effects of SVs in upcoming years.

Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.

Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies.

OBJECTIVE: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. METHODS: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. RESULTS: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. SIGNIFICANCE: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.

Functional genotype-phenotype associations in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.

Multimarker omnibus tests by leveraging individual marker summary statistics from large biobanks.

As biobanks become increasingly popular, access to genotypic and phenotypic data continues to increase in the form of precomputed summary statistics (PCSS). Widespread accessibility of PCSS alleviates many issues related to biobank data, including that of data privacy and confidentiality, as well as high computational costs. However, questions remain about how to maximally leverage PCSS for downstream statistical analyses. Here we present a novel method for testing the association of an arbitrary number of single nucleotide variants (SNVs) on a linear combination of phenotypes after adjusting for covariates for common multimarker tests (e.g., SKAT, SKAT-O) without access to individual patient-level data (IPD). We validate exact formulas for each method, and demonstrate their accuracy through simulation studies and an application to fatty acid phenotypic data from the Framingham Heart Study.

The structure of associations: Method insights from analyzing 28 clinical isolates of Cryptococcus neoformans.

Clinical isolates of a fungal pathogen from a single region or country often exhibit structural clonality or phylogenetic clustering at the sequence or MLST level; such population structure can persist also in larger samples. In efforts to improve causal understanding of pathogenesis at the molecular level, genome-wide association screening methods initially designed for other kingdoms have been applied to fungi. The example of a Colombian dataset of 28 clinical Cryptococcus neoformans VNI isolates indicates where the output from standard pipelines may need to be analyzed in new ways in order to efficiently extract hypotheses for experiments from fungal genotype-phenotype data.

Collections of clinical isolates of a human fungal pathogen can consist of clusters of genetically similar isolates. Such clustering complicates the screening for genetic associations with clinically relevant traits. We propose new methods, illustrating them for the fungus causing cryptococcosis.

Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.

PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.

Genetic basis of growth reaction to drought stress differs in contrasting high-latitude treeline ecotones of a widespread conifer.

Climate change is increasing the frequency and intensity of drought events in many boreal forests. Trees are sessile organisms with a long generation time, which makes them vulnerable to fast climate change and hinders fast adaptations. Therefore, it is important to know how forests cope with drought stress and to explore the genetic basis of these reactions. We investigated three natural populations of white spruce (Picea glauca) in Alaska, located at one drought-limited and two cold-limited treelines with a paired plot design of one forest and one treeline plot. We obtained individual increment cores from 458 trees and climate data to assess dendrophenotypes, in particular the growth reaction to drought stress. To explore the genetic basis of these dendrophenotypes, we genotyped the individual trees at 3000 single nucleotide polymorphisms in candidate genes and performed genotype-phenotype association analysis using linear mixed models and Bayesian sparse linear mixed models. Growth reaction to drought stress differed in contrasting treeline populations. Therefore, the populations are likely to be unevenly affected by climate change. We identified 40 genes associated with dendrophenotypic traits that differed among the treeline populations. Most genes were identified in the drought-limited site, indicating comparatively strong selection pressure of drought-tolerant phenotypes. Contrasting patterns of drought-associated genes among sampled sites and in comparison to Canadian populations in a previous study suggest that drought adaptation acts on a local scale. Our results highlight genes that are associated with wood traits which in turn are critical for the establishment and persistence of future forests under climate change.

Genes underlying the evolution of tetrapod testes size.

BACKGROUND: Testes vary widely in mass relative to body mass across species, but we know very little about which genes underlie and contribute to such variation. This is partly because evidence for which genes are implicated in testis size variation tends to come from investigations involving just one or a few species. Contemporary comparative phylogenetic methods provide an opportunity to test candidate genes for their role in phenotypic change at a macro-evolutionary scale-across species and over millions of years. Previous attempts to detect genotype-phenotype associations across species have been limited in that they can only detect where genes have driven directional selection (e.g. brain size increase). RESULTS: Here, we introduce an approach that uses rates of evolutionary change to overcome this limitation to test whether any of twelve candidate genes have driven testis size evolution across tetrapod vertebrates-regardless of directionality. We do this by seeking a relationship between the rates of genetic and phenotypic evolution. Our results reveal five genes (Alkbh5, Dmrtb1, Pld6, Nlrp3, Sp4) that each have played unique and complex roles in tetrapod testis size diversity. In all five genes, we find strong significant associations between the rate of protein-coding substitutions and the rate of testis size evolution. Such an association has never, to our knowledge, been tested before for any gene or phenotype. CONCLUSIONS: We describe a new approach to tackle one of the most fundamental questions in biology: how do individual genes give rise to biological diversity? The ability to detect genotype-phenotype associations that have acted across species has the potential to build a picture of how natural selection has sculpted phenotypic change over millions of years.

Rapid repeatable phenotypic and genomic adaptation following multiple introductions.

Uncovering the genomic basis of repeated adaption can provide important insights into the constraints and biases that limit the diversity of genetic responses. Demographic processes such as admixture or bottlenecks affect genetic variation underlying traits experiencing selection. The impact of these processes on the genetic basis of adaptation remains, however, largely unexamined empirically. We here test repeatability in phenotypes and genotypes along parallel climatic clines within the native North American and introduced European and Australian Ambrosia artemisiifolia ranges. To do this, we combined multiple lines of evidence from phenotype-environment associations, FST -like outlier tests, genotype-environment associations and genotype-phenotype associations. We used 853 individuals grown in common garden from 84 sampling locations, targeting 19 phenotypes, >83 k SNPs and 22 environmental variables. We found that 17%-26% of loci with adaptive signatures were repeated among ranges, despite alternative demographic histories shaping genetic variation and genetic associations. Our results suggest major adaptive changes can occur on short timescales, with seemingly minimum impacts due to demographic changes linked to introduction. These patterns reveal some predictability of evolutionary change during range expansion, key in a world facing ongoing climate change, and rapid invasive spread.

Different tradeoffs result from alternate genetic adaptations to a common environment.

Fitness tradeoffs are often assumed by evolutionary theory, yet little is known about the frequency of fitness tradeoffs during stress adaptation. Even less is known about the genetic factors that confer these tradeoffs and whether alternative adaptive mutations yield contrasting tradeoff dynamics. We addressed these issues using 114 clones of Escherichia coli that were evolved independently for 2,000 generations under thermal stress (42.2 °C). For each clone, we measured their fitness relative to the ancestral clone at 37 °C and 20 °C. Tradeoffs were common at 37 °C but more prevalent at 20 °C, where 56% of clones were outperformed by the ancestor. We also characterized the upper and lower thermal boundaries of each clone. All clones shifted their upper boundary to at least 45 °C; roughly half increased their lower niche boundary concomitantly, representing a shift of thermal niche. The remaining clones expanded their thermal niche by increasing their upper limit without a commensurate increase of lower limit. We associated these niche dynamics with genotypes and confirmed associations by engineering single mutations in the rpoB gene, which encodes the beta subunit of RNA polymerase, and the rho gene, which encodes a termination factor. Single mutations in the rpoB gene exhibit antagonistic pleiotropy, with fitness tradeoffs at 18 °C and fitness benefits at 42.2 °C. In contrast, a mutation within the rho transcriptional terminator, which defines an alternative adaptive pathway from that of rpoB, had no demonstrable effect on fitness at 18 °C. This study suggests that two different genetic pathways toward high-temperature adaptation have contrasting effects with respect to thermal tradeoffs.

Comparative genomics of the mimicry switch in Papilio dardanus.

The African Mocker Swallowtail, Papilio dardanus, is a textbook example in evolutionary genetics. Classical breeding experiments have shown that wing pattern variation in this polymorphic Batesian mimic is determined by the polyallelic H locus that controls a set of distinct mimetic phenotypes. Using bacterial artificial chromosome (BAC) sequencing, recombination analyses and comparative genomics, we show that H co-segregates with an interval of less than 500 kb that is collinear with two other Lepidoptera genomes and contains 24 genes, including the transcription factor genes engrailed (en) and invected (inv). H is located in a region of conserved gene order, which argues against any role for genomic translocations in the evolution of a hypothesized multi-gene mimicry locus. Natural populations of P. dardanus show significant associations of specific morphs with single nucleotide polymorphisms (SNPs), centred on en. In addition, SNP variation in the H region reveals evidence of non-neutral molecular evolution in the en gene alone. We find evidence for a duplication potentially driving physical constraints on recombination in the lamborni morph. Absence of perfect linkage disequilibrium between different genes in the other morphs suggests that H is limited to nucleotide positions in the regulatory and coding regions of en. Our results therefore support the hypothesis that a single gene underlies wing pattern variation in P. dardanus.

Genotype-phenotype spectrum and correlation of PHARC Syndrome due to pathogenic ABHD12 variants.

BACKGROUND: A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. METHODS: Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. RESULTS: Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. CONCLUSIONS: The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.

Improving the classification of cardinality phenotypes using collections.

MOTIVATION: Phenotypes are observable characteristics of an organism and they can be highly variable. Information about phenotypes is collected in a clinical context to characterize disease, and is also collected in model organisms and stored in model organism databases where they are used to understand gene functions. Phenotype data is also used in computational data analysis and machine learning methods to provide novel insights into disease mechanisms and support personalized diagnosis of disease. For mammalian organisms and in a clinical context, ontologies such as the Human Phenotype Ontology and the Mammalian Phenotype Ontology are widely used to formally and precisely describe phenotypes. We specifically analyze axioms pertaining to phenotypes of collections of entities within a body, and we find that some of the axioms in phenotype ontologies lead to inferences that may not accurately reflect the underlying biological phenomena. RESULTS: We reformulate the phenotypes of collections of entities using an ontological theory of collections. By reformulating phenotypes of collections in phenotypes ontologies, we avoid potentially incorrect inferences pertaining to the cardinality of these collections. We apply our method to two phenotype ontologies and show that the reformulation not only removes some problematic inferences but also quantitatively improves biological data analysis.

Weak genetic differentiation but strong climate-induced selective pressure toward the rear edge of mountain pine in north-eastern Spain.

Local differentiation at distribution limits may influence species' adaptive capacity to environmental changes. However, drivers, such gene flow and local selection, are still poorly understood. We focus on the role played by range limits in mountain forests to test the hypothesis that relict tree populations are subjected to genetic differentiation and local adaptation. Two alpine treelines of mountain pine (Pinus uncinata Ram. ex DC) were investigated in the Spanish Pyrenees. Further, an isolated relict population forming the species' southernmost distribution limit in north-eastern Spain was also investigated. Using genotyping by sequencing, a genetic matrix conformed by single nucleotide polymorphisms (SNPs) was obtained. This matrix was used to perform genotype-environment and genotype-phenotype associations, as well as to model risk of non-adaptedness. Increasing climate seasonality appears as an essential element in the interpretation of SNPs subjected to selective pressures. Genetic differentiations were overall weak. The differences in leaf mass area and radial growth rate, as well as the identification of several SNPs subjected to selective pressures, exceeded neutral predictions of differentiation among populations. Despite genetic drift might prevail in the isolated population, the Fst values (0.060 and 0.066) showed a moderate genetic drift and Nm values (3.939 and 3.555) indicate the presence of gene flow between the relict population and both treelines. Nonetheless, the SNPs subjected to selection pressures provide evidences of possible selection in treeline ecotones. Persistence in range boundaries seems to involve several selective pressures in species' traits, which were significantly related to enhanced drought seasonality at the limit of P. uncinata distribution range. We conclude that gene flow is unlikely to constrain adaptation in the P. uncinata rear edge, although this species shows vulnerability to future climate change scenarios involving warmer and drier conditions.

Tree-Level Growth Patterns and Genetic Associations Depict Drought Legacies in the Relict Forests of Abies marocana.

The frequency and intensity of drought events are increasing worldwide, challenging the adaptive capacity of several tree species. Here, we evaluate tree growth patterns and climate sensitivity to precipitation, temperature, and drought in the relict Moroccan fir Abies marocana. We selected two study sites, formerly stated as harboring contrasting A. marocana taxa (A. marocana and A. tazaotana, respectively). For each tree, dendrochronological methods were applied to quantify growth patterns and climate-growth sensitivity. Further, ddRAD-seq was performed on the same trees and close saplings to obtain single nucleotide polymorphisms (SNPs) and related genotype-phenotype associations. Genetic differentiation between the two studied remnant populations of A. marocana was weak. Growth patterns and climate-growth relationships were almost similar at the two sites studied, supporting a negative effect of warming. Growth trends and tree size showed associations with SNPs, although there were no relationships with phenotypes related to climatic sensitivity. We found significant differences in the SNPs subjected to selection in the saplings compared to the old trees, suggesting that relict tree populations might be subjected to genetic differentiation and local adaptation to climate dryness. Our results illustrate the potential of tree rings and genome-wide analysis to improve our understanding of the adaptive capacity of drought-sensitive forests to cope with ongoing climate change.

Genome-wide genotype-phenotype associations in microbes.

The concept of a gene has been developed a lot since the Mendelian era owing to the rapid progress in molecular biology and informatics. To explore the nature of life, varieties of biological tools have been continuously established. Many achievements have been made to clarify the relationships between genotypes and phenotypes. However, it is still not completely clear that how traits of an organism are encoded by its genome. In this review, we will summarize and discuss representative works in systematical functional genomic studies in microbes. By analyzing their developmental progressions and limitations, we may have chances to design more powerful means to decipher the code of life.

Genotype-phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients.

AIMS: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders. Although, several genotype-phenotype studies have carried out on HSPs, the association between genotypes and clinical phenotypes remain incomplete since most studies are small in size or restricted to a few genes. Accordingly, this study provides the systematic meta-analysis of genotype-phenotype associations in HSP. METHODS AND RESULTS: We retrieved literature on genotype-phenotype associations in patients with HSP and mutated SPAST, REEP1, ATL1, SPG11, SPG15, SPG7, SPG35, SPG54, SPG5. In total, 147 studies with 13,570 HSP patients were included in our meta-analysis. The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients. As for AR-HSP patients, the rates of mutations in SPG11 (18%), SPG15 (7%) and SPG7 (13%) were higher than SPG5 (5%), as well as SPG35 (8%) and SPG54 (7%). The mean age of AD-HSP onset for ATL1 mutation-positive patients was earlier than patients with SPAST, REEP1 mutations. Also, the tendency toward younger age at AR-HSP onset for SPG35 was higher than other mutated genes. It is noteworthy that the mean age at HSP onset ranged from infancy to adulthood. As for the gender distribution, the male proportion in SPG7-HSP (90%) and REEP1-HSP (78%) was markedly high. The frequency of symptoms was varied among patients with different mutated genes. The rates of LL weakness, superficial sensory abnormalities, neuropathy, and deep sensory impairment were noticeably high in REEP1 mutations carriers. Also, in AR-HSP patients with SPG11 mutations, the presentation of symptoms including pes cavus, Neuropathy, and UL spasticity was higher. CONCLUSION: Our comprehensive genotype-phenotype assessment of available data displays that the mean age at disease onset and particular sub-phenotypes are associated with specific mutated genes which might be beneficial for a diagnostic procedure and differentiation of the specific mutated genes phenotype among diverse forms of HSP.

Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. OBJECTIVE: We tested if genetic variants in part explain the heterogeneity in DLB. METHODS: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aß1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. RESULTS: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. CONCLUSION: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.

Is FMR1 CGG Repeat Number Polymorphism Associated With Phenotypic Variation in the General Population? Report From a Cohort of 5,499 Adults.

FMR1 CGG repeat length was assayed in 5499 research participants (2637 men and 2862 women) in the Wisconsin Longitudinal Study (WLS), a population-based cohort. Most past research has focused on clinically-ascertained individuals with expansions in CGG repeats, either those with fragile X syndrome (> 200 CGG repeats), the FMR1 premutation (55-200 repeats), or in the gray zone (variously defined as 45-54 or 41-54 repeats). In contrast, the WLS is a unique source of data that was obtained from an unselected cohort of individuals from the general population for whom FMR1 CGG repeat length was assayed. The WLS is a random sample of one-third of all high school seniors in the state of Wisconsin in 1957. The most recent round of data collection was in 2011; thus, the study spanned over 50 years. Saliva samples were obtained from 69% of surviving members of the cohort in 2008 and 2011, from which CGG repeats were assayed. With one exception, the CGG repeat length of all members of this cohort was below 100 (ranging from 7 to 84). The present study evaluated the genotype-phenotype associations of CGG repeat number and IQ, college graduation, age at menopause, number of biological children, having a child with intellectual or developmental disabilities, and the likelihood of experiencing an episode of depression during adulthood. Linear and curvilinear effects were probed. Although effect sizes were small, significant associations were found between CGG repeat length and high school IQ score, college graduation, number of biological children, age at menopause, and the likelihood of having an episode of depression. However, there was no significant association between repeat length and having a child diagnosed with an IDD condition. This study demonstrates a continuum of phenotype effects with FMR1 repeat lengths and illustrates how research inspired by a rare genetic condition (such as fragile X syndrome) can be used to probe genotype-phenotype associations in the general population.