Mats Larsson

Affiliated (see below). · I am affiliated with Prof. Nick Martins research group at QIMR Berghofer in Brisbane, Australia and Prof. Susan Walsh research group at Indiana University Purdue University Indianapolis, IUPUI, USA.
16.04 · Doctor of Philosophy (speciality Behavior Genetics)
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Introduction
I’m affiliated with Prof Nick Martin's research group at QIMR Berghofer in Brisbane, Australia and Prof Susan Walsh's research group at Indiana University Purdue University Indianapolis, IUPUI, USA. Currently, I try to replicate my previous iris GWAS findings in a larger sample (N>9000) showing that orthologous human up- and downregulated dopaminergic genes in the medial forebrain of mice was enriched for crypt and furrows. Hence, enrichment tests for human cortical structures will be executed.
Current institution
Affiliated (see below).
I am affiliated with Prof. Nick Martins research group at QIMR Berghofer in Brisbane, Australia and Prof. Susan Walsh research group at Indiana University Purdue University Indianapolis, IUPUI, USA.
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Research Associate
Skills and Expertise
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Ondokuz Mayıs Üniversitesi
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Icahn School of Medicine at Mount Sinai
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The University of Sydney
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Jagiellonian University
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Variable and person-oriented analyses were used to explore the associations between personality and three previously untested general iris characteristics: crypts, pigment dots and contraction furrows. Personality data, as measured by the NEO PI-R and ratings of iris characteristics from 428 undergraduate students were collected. Crypts were significantly associated with five approach-related behaviors, i.e., feelings, tendermindedness, warmth, trust and positive emotions, whereas furrows were associated with impulsiveness. These findings suggest that because Pax6 induces tissue deficiencies in both the iris and the left anterior cingulate cortex, Pax6 may influence the extent people engage in approach-related behaviors. The results from using a person-oriented analysis suggested that people with different iris configurations tend to develop along different personality trajectories. Future longitudinal studies, twin-studies and genetic association studies, may benefit from collecting iris data and testing candidate genes for crypts and furrows.
Human iris patterns are highly variable. The origins of this variation are of interest in the study of iris-related eye diseases and forensics, as well as from an embryological developmental perspective, with regard to their possible relationship to fundamental processes of neurodevelopment. We have performed genome-wide association scans on four iris characteristics (crypt frequency, furrow contractions, presence of peripupillary pigmented ring, and number of nevi) in three Australian samples of European descent. Both the discovery (n = 2121) and replication (n = 499 and 73) samples showed evidence for association between (1) crypt frequency and variants in the axonal guidance gene SEMA3A (p = 6.6 × 10(-11)), (2) furrow contractions and variants within the cytoskeleton gene TRAF3IP1 (p = 2.3 × 10(-12)), and (3) the pigmented ring and variants in the well-known pigmentation gene SLC24A4 (p = 7.6 × 10(-21)). These replicated findings individually accounted for around 1.5%-3% of the variance for these iris characteristics. Because both SEMA3A and TRAFIP1 are implicated in pathways that control neurogenesis, neural migration, and synaptogenesis, we also examined the evidence of enhancement among such genes, finding enrichment for crypts and furrows. These findings suggest that genes involved in normal neuronal pattern development may also influence tissue structures in the human iris.
The presence of melanin pigment within the iris is responsible for the visual impression of human eye colouration with complex patterns also evident in this tissue, including Fuchs' crypts, nevi, Wolfflin nodules and contraction furrows. The genetic basis underlying the determination and inheritance of these traits has been the subject of debate and research from the very beginning of quantitative trait studies in humans. Although segregation of blue-brown eye colour has been described using a simple Mendelian dominant-recessive gene model this is too simplistic, and a new molecular genetic perspective is needed to fully understand the biological complexities of this process as a polygenic trait. Nevertheless, it has been estimated that 74% of the variance in human eye colour can be explained by one interval on chromosome 15 that contains the OCA2 gene. Fine mapping of this region has identified a single base change rs12913832 T/C within intron 86 of the upstream HERC2 locus that explains almost all of this association with blue-brown eye colour. A model is presented whereby this SNP, serving as a target site for the SWI/SNF family member HLTF, acts as part of a highly evolutionary conserved regulatory element required for OCA2 gene activation through chromatin remodelling. Major candidate genes possibly effecting iris patterns are also discussed, including MITF and PAX6.
The relative importance of genetic influences (heritability) on five general textural quality characteristics of the human iris was assessed using sex and age limitation models. Colour photographs of irises were available from 100 monozygotic twin pairs, 99 dizygotic twin pairs, and 99 unrelated randomly paired age-matched German subjects. Comparative scales were constructed and two judges who were blind to zygosity independently rated five characteristic of the subjects' left iris. Inter-rater reliabilities were larger than.90 for all five scales. The heritabilities for the five iris characteristics ranged from.51-.90. No sex-specific genetic factors were found for the iris characteristics. Age-group differences in heritability were found for one of the five iris characteristics - "distinction of white dot rings". Heritability was greater for the older cohort (90%) than the younger (73%). The iris characteristics that showed the next highest additive-genetic effect were "contractional furrows" (78%) and "frequency of crypts" in the main stroma leaf (66%).
To estimate the magnitude of genetic correlations among five general textural characteristics of the human iris. Color photographs of iris were available from 100 monozygotic and 99 dizygotic twin pairs. Comparative scales were constructed based on ratings of the subjects' left iris. To explore the genetic and environmental covariation among frequency of Fuchs' crypts, frequency of pigment dots, iris color, the extension, and distinction of Wolfflin nodules, and contraction furrows, a structural equation model with Cholesky decomposition was applied to variance-covariance matrices for monozygotic (MZ) and dizygotic (DZ) pairs. Significant genetic correlations fell between -0.22 and 0.44 and accounted almost entirely for the phenotypic correlations among the iris characteristics. No evidence for individual specific environmental effects in common to the characteristics was found. The modest genetic correlations indicate that there is little overlap in the genetic influence for these characteristics. Candidate genes with embryological and histological expression patterns in the eye could potentially influence the iris characteristics' variability.
The human iris is one of the most important identifiable features that contain many complex patterns. In this work, we attempted to automatically classify irises with machine learning models based on several different iris patterns in order to assist genetic research related to pigmentation and structural tissue differences within the human iris. Specifically, two main iris patterns that are commonly observed in the general population were analyzed: the Fuchs’ crypts and the peripupillary pigmented ring. A two-stage machine learning model was proposed to classify the iris crypt frequency, in which a Mask R-CNN model was first built to identify the number of crypts of each size level in the iris, followed by a SVM model to determine the final category. Another KNN model, which used the area-refined histogram features, was applied to classify the iris based on the peripupillary pigmented ring. The labels used in the images were generated independently by two trained expert raters. The performance of these models was evaluated on a test set with overall accuracies of the models estimated at 80.0% and 86.6% for crypts and pigmented ring, respectively. These optimized objective models were therefore concordant with the inter-rater reliability scores produced by expert human raters.
You may find Gonçalo's Software and VEGAS (Versatile Gene-based Association Study) useful.
The effect of LD on SNP interaction analysis. 10,000 pairs of SNPs in LD (r2>0.5) and 10,000 pairs of SNPs not in LD (r2<0.01) were randomly selected over the genome and tested for interaction with the permutated color traits using F-test specified in the method section. The observed P values on the −log10(P) scale derived without LD (blue circle) or with LD (red plus) are plotted against the expected ones under the null distribution of no interaction. (0.39 MB TIF)
Significant SNP interactions on eye color. SNPs having significant interaction effect on eye color are depicted using box-and-whisker diagrams. Color H and S distributions are grouped by cross genotypes of 2 interacting SNPs. Distribution summaries include min-max range (black dotted vertical line), lower-upper 25% quartile range (blue box), and median (red line). Observations outside of 1.5 folds of the quartile range are indicated using red pluses. (0.34 MB TIF)
SNP interaction analysis. Pair-wise SNP-SNP interactions of 64 SNPs preselected from known eye color genes and in 3 novel loci identified in the current study. SNPs are indexed according to Table S1, sorted according to chromosome and physical positions. The high LD regions include LYST (SNPs 1–2), SLC45A2 (3–4), IRF4 (5–6), TYRP1 (7–16), TYR (17–23), SLC24A4 (24–27), OCA2/HERC2 (28–57), 17q25.3 (58–59), TTC3/DSCR9 (60–64). The lower right triangle represents the significance of interaction on the −log10(P) scale; all P values smaller than 10−10 are truncated at 10−10. The upper triangle are the linkage disequilibrium r2 values×10. (A) Hue, (B) Saturation. (2.95 MB TIF)
SNPs ascertained for pair-wise interaction analysis and P values from single SNP analysis in the Rotterdam Study (RS123). (0.11 MB DOC)
Interaction analysis. (0.04 MB DOC)
Genotype quality control. (A) Genotypes from 120 HapMap Phase 2 subjects were merged with the RS3 samples. QCs of RS1 and RS2 samples have been described in detail previously. The first 2 principal components derived from multidimensional decomposition analysis of the 1-IBS matrix are depicted. Blue circles represent the HapMap European (CEU) samples, green circles are the HapMap East Asian (CHB+JPT) samples, and red circles represent the HapMap West African (YRI) samples. Black and Grey circles are samples from RS3. In total 112 RS3 samples outside of 4 standard deviations of the principle component of the CEU samples were removed. (B) RS1, RS2, and RS3 samples were merged after excluding outliers in separate quality control procedures. The first 2 principal components are depicted. Red circles are the RS1 samples, blue circles are RS2 samples, and green circles are the RS3 samples. No outliers were identified. (1.10 MB TIF)
Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.
This dissertation explains why behavioral genetic research can be better informed by using characteristics in the human iris as biomarkers for personality, and is divided into five parts. Part I gives an introduction to the classical twin method and an overview of the findings that have led most developmental researchers to recognize that the normal variation of personality depends on a complex interplay between genetic and environmental factors. Part II highlights empirical findings that, during the last twenty years, have gradually moved genetic and environmental theory and research to evolve toward one another, and also presents the theory of genetics and experience that currently is used to explain how the interplay between genes and the environment works. Part III explains why, from a developmental perspective, it is of interest to identify candidate genes for personality, and gives a brief overview of genes that have been associated with personality. Problems associated with genetic research on the molecular level and how these apply to personality are also highlighted. Part IV examines molecular research on the iris and the brain, which suggests that genes expressed in the iris may be associated with personality, and explains how the use of iris characteristics and a person-oriented methodology can increase power to test candidate genes for personality by taking advantage of the self-organizing properties of the nervous system. The empirical foundation for the questions posed in this dissertation and also the empirical results are presented here. Part V discusses the associations found between iris characteristics and personality, and exemplifies how iris characteristics can be used within the theoretical frameworks presented in parts I, II, III and IV. In other words, Part V explains how iris characteristics and a personoriented methodology – as well as identifying, and increasing power to test candidate genes for personality - can be used to investigate how people’s experiences in themselves are influenced by genetic factors.
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