Biology subjects

Fisher, S. E.

Publications and source records attributed to Fisher, S. E..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Neuroimaging genomics as a window into the evolution of human sulcal organization

Primate brain evolution has involved prominent expansions of the cerebral cortex, with largest effects observed in the human lineage. Such expansions were accompanied by fine-grained anatomical alterations, including increased cortical folding. However, the molecular bases of evolutionary alterations in human sulcal organisation are not yet well understood. Here, we integrated data from recently completed large-scale neuroimaging genetic analyses with annotations of the human genome relevant to various periods and events in our evolutionary history. These analyses identified single-nucleotide polymorphism (SNP) heritability enrichments in foetal brain human-gained enhancer elements for a number of sulcal structures, including the central sulcus, which is implicated in human hand dexterity. We zeroed-in on a genomic region which harbours DNA variants associated with left central sulcus shape, a human-gained enhancer element, and genetic loci involved in neurogenesis including ZIC4, to illustrate the value of this approach for probing the complex factors contributing to human sulcal evolution.

neuroscience↗

bioRxiv2023

Pervasive inter-individual differences in the sensorimotor-association axis of cortical organization

In humans, many neurobiological features of the cortex--including gene expression patterns, microstructure, and functional connectivity--vary systematically along a sensorimotor-association (S-A) axis of brain organisation. To date, it is still poorly understood whether inter-individual differences in patterns of S-A axis capture these robust spatial relationships across neurobiological properties observed at the group-level. Here, we examine inter-individual differences in structural and functional properties of the S-A axis, namely cortical microstructure, geodesic distances, and the functional gradient, in a sample of young adults from the Human Connectome Project (N = 992, including 328 twins). We quantified heritable variation associated with inter-individual differences in the S-A axis, and assessed whether structural and functional properties that are highly spatially correlated at the group-level also share genetic underpinnings. To consider measurement errors in resting-state functional connectivity data and their impact on properties of the S-A axis, we used a multivariate twin design capable of disentangling individual-level variation in both intra- and inter-individual differences. After accounting for some of the intra-individual variation, we found average heritable individual differences in both the functional gradient (htwin2 = 57%), cortical microstructure (htwin2 = 43%), and geodesic distances (htwin2 = 34%). However, these genetic influences were mostly distinct and deviated from group-level patterns. In particular, we found no significant genetic correlation between the functional gradient and microstructure, while we found both positive and negative genetic associations between the functional gradient and geodesic distances. Our approach highlights the complexity of genetic contributions to brain organisation and may have potential implications for understanding cognitive variability within the S-A axis framework.

neuroscience↗

bioRxiv2023

Exome-wide analysis implicates rare protein-altering variants in human handedness

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examined whether left-handedness is also influenced by rare coding variants (frequencies [≤] 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals (UK Biobank). The beta-tubulin gene TUBB4B showed exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers (0.076%) than right-handers (0.028%). The TUBB4B variants were mostly heterozygous missense changes, but included two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 showed evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study revealed a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

genetics↗

bioRxiv2023

Normative Modeling of Brain Morphometry Across the Lifespan using CentileBrain: Algorithm Benchmarking and Model Optimization

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

bioinformatics↗

bioRxiv2022

Genomic contributions to infant and toddler vocabulary scores: Implications for association with health-, cognition- and behaviour-related outcomes

BackgroundThe number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors, although mechanisms are not well understood. Here, we performed a meta-genome-wide association study within the EAGLE consortium and investigated polygenic overlap with later-life traits, including Attention-Deficit/Hyperactivity Disorder (ADHD) and cognition. MethodsWe studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h2), genetic correlations (rg) and modelled underlying genetic factor structures with multivariate models. ResultsContributions of common genetic variation to early-life vocabulary were modest (SNP-h2: 0.08(SE=0.01) to 0.24(SE=0.03)) and multi-factorial. Genetic overlap between infant expressive and toddler receptive vocabulary was near zero (rg=0.07(SE=0.10)), although both measures were genetically related to toddler expressive vocabulary (rg=0.69(SE=0.14) and rg=0.67(SE=0.16), respectively). Consistently, polygenic association patterns with later-life traits differed: Genetic links with cognition emerged only in toddlerhood (e.g. toddler receptive vocabulary and intelligence: rg=0.36(SE=0.12)), despite comparable study power for infant measures. Furthermore, increased polygenic ADHD risk was associated with larger infant expressive vocabulary (rg=0.23(SE=0.08)), as confirmed by ADHD-symptom-based follow-up analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC-rg=0.54(SE=0.26)). Genetic relationships with toddler receptive vocabulary were, however, opposite (ALSPAC-rg=-0.74(SE=0.23)), highlighting developmental changes in genetic architectures. ConclusionsMultiple genetic components contribute to early-life vocabulary development, shaping polygenic association patterns with later-life ADHD symptoms and cognition.

genomics↗

bioRxiv2022

Genetic architecture of the white matter connectome of the human brain

White matter tracts form the structural basis of large-scale functional networks in the human brain. We applied brain-wide tractography to diffusion images from 30,810 adult participants (UK Biobank), and found significant heritability for 90 regional connectivity measures and 851 tract-wise connectivity measures. Multivariate genome-wide association analyses identified 355 independently associated lead SNPs across the genome, of which 77% had not been previously associated with human brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia and neurons. We used the multivariate association profiles of lead SNPs to identify 26 genomic loci implicated in structural connectivity between core regions of the left-hemisphere language network, and also identified 6 loci associated with hemispheric left-right asymmetry of structural connectivity. Polygenic scores for schizophrenia, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, left-handedness, Alzheimers disease, amyotrophic lateral sclerosis, and epilepsy showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to the structural connectome of the human brain in the general adult population, highlighting links with polygenic disposition to brain disorders and behavioural traits. One sentence summaryVariability in white matter fiber tracts of the human brain is associated with hundreds of newly discovered genomic loci that especially implicate stem, neural and glial cells during prenatal development, and is also associated with polygenic dispositions to various brain disorders and behavioural traits.

neuroscience↗

bioRxiv2022

Dissociable Cellular and Genetic Mechanisms of Cortical Thinning at Different Life Stages

Mechanisms underpinning age-related variations in cortical thickness in the human brain remain poorly understood. We investigated whether inter-regional age-related variations in cortical thinning (in a multicohort neuroimaging dataset from the ENIGMA Lifespan Working Group totalling 14,248 individuals, aged 4-89 years) depended on cell-specific marker gene expression levels. We found differences amidst early-life (<20 years), mid-life (20-60 years), and late-life (>60 years) in the patterns of association between inter-regional profiles of cortical thickness and expression profiles of marker genes for CA1 and S1 pyramidal cells, astrocytes, and microglia. Gene ontology and enrichment analyses indicated that each of the three life-stages was associated with different biological processes and cellular components: synaptic modeling in early life, neurotransmission in mid-life, and neurodegeneration in late-life. These findings provide mechanistic insights into age-related cortical thinning during typical development and aging.

neuroscience↗

bioRxiv2021

High-precision spatial analysis of mouse courtship vocalization behavior reveals sex and strain differences

Mice display a wide repertoire of vocalizations that varies with sex, strain, and context. Especially during social interaction, mice emit sequences of ultrasonic vocalizations (USVs) of high complexity. As animals of both sexes vocalize, a reliable attribution of USVs to their emitter is essential. The state-of-the-art in sound localization for USVs in 2D allows spatial localization at a resolution of multiple centimeters. However, animals interact at closer ranges, e.g. snout-to-snout. Hence, improved algorithms are required to reliably assign USVs. We present a novel algorithm, SLIM (Sound Localization via Intersecting Manifolds), that achieves a 3-fold improvement in accuracy (12-14.3mm) using only 4 microphones and extends to many microphones and localization in 3D. This accuracy allows reliable assignment of 84.3% of all USVs in our dataset. We apply SLIM to courtship interactions between adult C57Bl/6J wildtype mice and those carrying a heterozygous Foxp2 variant (R552H). The improved spatial accuracy reveals detailed vocalization preferences for specific spatial relations between the mice. Specifically, vocalization probability, duration, Wiener entropy, and frequency level differed in particular spatial relations between WT females, Foxp2-R552H and WT males. In conclusion, the improved attribution of vocalizations to their emitters provides a foundation for better understanding social vocal behaviors.

animal behavior and cognition↗

bioRxiv2021

Genetic variations within human gained enhancer elements affect human brain sulcal morphology.

The expansion of the cerebral cortex is one of the most distinctive changes in the evolution of the human brain. Cortical expansion and related increases in cortical folding may have contributed to emergence of our capacities for high-order cognitive abilities. Molecular analysis of humans, archaic hominins, and non-human primates has allowed identification of chromosomal regions showing evolutionary changes at different points of our phylogenetic history. In this study, we assessed the contributions of genomic annotations spanning 30 million years to human sulcal morphology measured via MRI in more than 18,000 participants from the UK Biobank. We found that variation within brain-expressed human gained enhancers, regulatory genetic elements that emerged since our last common ancestor with Old World monkeys, explained more trait heritability than expected for the left and right calloso-marginal posterior fissures and the right central sulcus. Intriguingly, these are sulci that have been previously linked to the evolution of locomotion in primates and later on bipedalism in our hominin ancestors.

neuroscience↗

bioRxiv2021

Left-handedness and its genetic influences are associated with structural asymmetries mapped across the cerebral cortex in 31,864 individuals

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We re-sampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers and right-handers showed average differences of surface area asymmetry within fusiform, anterior insular, anterior-middle-cingulate and precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2 and NME7 - the latter is mutated in left-right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas non-heritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

neuroscience↗

bioRxiv2020

The developmental genetic architecture of vocabulary skills during the first three years of life: Capturing emerging associations with later-life reading and cognition

Individual differences in early-life vocabulary measures are heritable and associated with subsequent reading and cognitive abilities, although the underlying mechanisms are little understood. Here, we (i) investigate the developmental genetic architecture of expressive and receptive vocabulary in toddlerhood and (ii) assess origin and developmental stage of emerging genetic associations with mid-childhood verbal and non-verbal skills. Studying up to 6,524 unrelated children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort, we dissected the phenotypic variance of longitudinally assessed early-life vocabulary measures (15-38 months) and later-life reading and cognitive skills (7-8 years) into genetic and residual components, by fitting multivariate structural equation models to genome-wide genetic-relationship matrices. Our findings show that the genetic architecture of early-life vocabulary is dynamic, involving multiple distinct genetic factors. Two of them are developmentally stable and contribute to genetic variation in mid-childhood skills: Genetic links with later-life verbal abilities (reading, verbal intelligence) emerged with expressive vocabulary at 24 months. The underlying genetic factor explained 10.1% variation (path coefficient: 0.32(SE=0.06)) in early language, but also 6.4% (path coefficient: 0.25(SE=0.12)) and 17.9% (path coefficient: 0.42(SE=0.13)) variation in mid-childhood reading and verbal intelligence, respectively. An independent stable genetic factor was identified for receptive vocabulary at 38 months, explaining 2.1% (path coefficient: 0.15(SE=0.07)) phenotypic variation. This genetic factor was also linked to both verbal and non-verbal cognitive abilities in mid-childhood, accounting for 24.7% of the variation in non-verbal intelligence (path coefficient: 0.50(SE=0.08)), 33.0% in reading (path coefficient: 0.57(SE=0.07)) and 36.1% in verbal intelligence (path coefficient: 0.60(0.10)), corresponding to the majority of genetic variance ([≥]66.4%). Thus, the genetic foundations of mid-childhood reading and cognition are diverse. They involve at least two independent genetic factors that emerge at different developmental stages during early language development and may implicate differences in cognitive processes that are already detectable during toddlerhood. Author summaryDifferences in the number of words young children produce (expressive vocabulary) and understand (receptive vocabulary) can be partially explained by genetic factors, and are related to reading and cognitive abilities later in life. Here, we studied genetic influences underlying word production and understanding during early development (15-38 months) and their genetic relationship with mid-childhood reading and cognitive skills (7-8 years), based on longitudinal phenotype measures and genome-wide genetic data from up to 6,524 unrelated children. We showed that vocabulary skills assessed at different stages during early development are influenced by distinct genetic factors, two of which also contribute to genetic variation in mid-childhood skills, suggesting developmental stability: Genetic sources emerging for word production skills at 24 months were linked to subsequent verbal abilities, including mid-childhood reading and verbal intelligence performance. A further independent genetic factor was identified that related to word comprehension at 38 months and also contributed to variation in later verbal as well as non-verbal abilities during mid-childhood. Thus, the genetic foundations of mid-childhood reading and cognition involve at least two independent genetic factors that emerge during early-life langauge development and may implicate differences in overarching cognitive mechanisms.

genetics↗

bioRxiv2020

The Multivariate Genetic Architecture of Literacy-, Language- and Working Memory-related Abilities as Captured by Genome-wide Variation

There is genetic overlap between many measures of literacy, language and phonological working memory (PWM) though our knowledge of multivariate genetic architectures is incomplete. Here, we directly modeled genetic trait interrelationships in unrelated UK youth (8-13 years, N=6,453), as captured by genome-wide relationship matrices, using novel structural equation modeling techniques. We identified, besides shared genetic factors across different domains (explaining 91-97% genetic variance in literacy-related measures such as passage reading fluency, spelling, phonemic awareness, 44% in oral language and 53% in PWM), evidence for distinct cognitive abilities; trait-specific genetic influences ranged between 47% for PWM to 56% for oral language. Among reading fluency measures (non-word, word and passage reading), single-word reading was genetically most diverse. Multivariate genetic and residual covariance patterns showed concordant effect directionality, except for near-zero residual correlations between oral language and literacy-related abilities. These findings suggest differences in etiological mechanisms and trait modifiability even among genetically highly correlated skills.

genetics↗

bioRxiv2020

Relations between hemispheric asymmetries of grey matter and auditory processing of spoken syllables in 281 healthy adults

Most people have a right-ear advantage for the perception of spoken syllables, consistent with left hemisphere dominance for speech processing. However, there is considerable variation, with some people showing left-ear advantage. The extent to which this variation is reflected in brain structure remains unclear. We tested for relations between hemispheric asymmetries of auditory processing and of grey matter in 281 adults, using dichotic listening and voxel-based morphometry. This was the largest study of this issue to date. Per-voxel asymmetry indexes were derived for each participant following registration of brain magnetic resonance images to a template that was symmetrized. The asymmetry index derived from dichotic listening was related to grey matter asymmetry in clusters of voxels corresponding to the amygdala and cerebellum lobule VI. There was also a smaller, non-significant cluster in the posterior superior temporal gyrus, a region of auditory cortex. These findings contribute to the mapping of asymmetrical structure-function links in the human brain, and suggest that subcortical structures should be investigated in relation to hemispheric dominance for speech processing, in addition to auditory cortex.

neuroscience↗

bioRxiv2020

Analysis of structural brain asymmetries in Attention-Deficit/Hyperactivity Disorder in 39 datasets

ObjectiveSome studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here we performed the largest-ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. MethodsWe analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,978 people with ADHD and unaffected 1,917 controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modelling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. ResultsThere was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.4, P=0.019). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.4, P=0.007) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohens d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. ConclusionPrior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

neuroscience↗

bioRxiv2019

The amplification of genetic factors for early vocabulary during children's language and literacy development

The heritability of language and literacy skills increases during development. The underlying mechanisms are little understood, and may involve (i) the amplification of early genetic influences and/or (ii) the emergence of novel genetic factors (innovation). Here, we use multivariate structural equation models to quantify these processes, as captured by genome-wide genetic markers. Studying expressive and receptive vocabulary at 38 months and subsequent language, literacy and cognitive skills (7-13 years) in unrelated children (ALSPAC: N[≤]6,092), we found little support for genetic innovation during mid-childhood and adolescence. Instead, genetic factors for early vocabulary, especially those unique to receptive skills, were amplified. Explaining as little as 3.9%(SE=1.8%) variation in early language, the same genetic influences accounted for 25.7%(SE=6.4%) to 45.1%(SE=7.6%) variation in verbal intelligence and literacy skills, but also performance intelligence, capturing the majority of SNP-heritability ([≤]99%). This suggests that complex verbal and non-verbal cognitive skills originate developmentaly in early receptive language.

genetics↗

bioRxiv2019

Handedness and Other Variables Associated with Human Brain Asymmetrical Skew

The human cerebral hemispheres show a left-right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, the UK Biobank (N = 39,678), Human Connectome Project (N = 1,113) and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional grey and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed SNP-based heritabilities of 4-13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in GWAS for either skew. There was evidence for a significant genetic correlation (rg=-0.40, p=0.0075) between horizontal brain skew and Autism Spectrum Disorder. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.

neuroscience↗

bioRxiv2019

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

Structural brain changes along the lineage that led to modern Homo sapiens have contributed to our unique cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens in living humans, to reveal how selective pressures have shaped neocortical surface area. We show that variation within human gained enhancers active in the developing brain is associated with global surface area as well as that of specific regions. Moreover, we find evidence of recent polygenic selection over the past 2,000 years influencing surface area of multiple cortical regions, including those involved in spoken language and visual processing.

neuroscience↗

bioRxiv2019

Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment

Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the proteins function and to be deleterious (rs41298373, P=2.01x10-15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54x10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.

genetics↗