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Kamitaki, Nolan

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Kamitaki

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Nolan

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Kamitaki, Nolan
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    Complement genes contribute sex-biased vulnerability in diverse disorders
    (Springer Science and Business Media LLC, 2020-05-11) Kamitaki, Nolan; Sekar, Aswin; Handsaker, Robert E.; de Rivera, Heather; Tooley, Katherine; Morris, David L.; Taylor, Kimberly E.; Whelan, Christopher W.; Tombleson, Philip; Loohuis, Loes M. Olde; Boehnke, Michael; Kimberly, Robert P.; Kaufman, Kenneth M.; Harley, John B.; Langefeld, Carl D.; Seidman, Christine; Pato, Michele T.; Pato, Carlos N.; Ophoff, Roel A.; Graham, Robert R.; Criswell, Lindsey A.; Vyse, Timothy J.; McCarroll, Steven
    Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men, whereas schizophrenia affects men more frequently and severely. All three illnesses have their strongest common genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus. Here we show that the complement component 4 (C4) genes, which are also in the MHC locus and were recently found to increase risk for schizophrenia, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10-117 in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59-30.89; p < 10-23 in total) among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (vs. 6-fold, 15-fold, and 1.26-fold among women respectively). At a protein level, both C4 and its effector C3 were present at greater levels in men than women in cerebrospinal fluid (p < 10-5 for both C4 and C3) and plasma among adults ages 20-50, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
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    A Rapid Molecular Approach for Chromosomal Phasing
    (Public Library of Science, 2015) Regan, John F.; Kamitaki, Nolan; Legler, Tina; Cooper, Samantha; Klitgord, Niels; Karlin-Neumann, George; Wong, Catherine; Hodges, Shawn; Koehler, Ryan; Tzonev, Svilen; McCarroll, Steven
    Determining the chromosomal phase of pairs of sequence variants – the arrangement of specific alleles as haplotypes – is a routine challenge in molecular genetics. Here we describe Drop-Phase, a molecular method for quickly ascertaining the phase of pairs of DNA sequence variants (separated by 1-200 kb) without cloning or manual single-molecule dilution. In each Drop-Phase reaction, genomic DNA segments are isolated in tens of thousands of nanoliter-sized droplets together with allele-specific fluorescence probes, in a single reaction well. Physically linked alleles partition into the same droplets, revealing their chromosomal phase in the co-distribution of fluorophores across droplets. We demonstrated the accuracy of this method by phasing members of trios (revealing 100% concordance with inheritance information), and demonstrate a common clinical application by phasing CFTR alleles at genomic distances of 11–116 kb in the genomes of cystic fibrosis patients. Drop-Phase is rapid (requiring less than 4 hours), scalable (to hundreds of samples), and effective at long genomic distances (200 kb).
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    Schizophrenia risk from complex variation of complement component 4
    (2016) Sekar, Aswin; Rosen, Allison; de Rivera, Heather; Bell, Avery; Hammond, Timothy; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matt; Van Doren, Vanessa; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert; Daly, Mark; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven
    Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals affected with schizophrenia.
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    Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
    (Springer Nature, 2017) Merkle, Florian; Ghosh, Sulagna; Kamitaki, Nolan; Mitchell, Jana; Avior, Yishai; Mello, Curtis; Kashin, Seva; Mekhoubad, Shila; Ilic, Dusko; Sweetnam, Maura; Saphier Belfer, Genevieve; Handsaker, Robert; Genovese, Giulio; Bar, Shiran; Benvenisty, Nissim; McCarroll, Steven; Eggan, Kevin
    Background: Depressive disorders are the second-leading cause of global disability, and an area of increasing focus in international health efforts. We describe a community health worker (CHW) program rolled out in a stepped-wedge design during the course of routine patient care to 74 patients with depression in 4 communities in rural Mexico. Methods: We used random effects models to calculate the change in Patient Health Questionnaire-9 (PHQ-9) scores, an internationally validated measure of depression, before and after the CHW program was introduced. As a secondary outcome, we also examined the change pre- and post-intervention in the proportion of patients who had a mean of at least one visit per month for depression follow-up, in accordance with clinic visit guidelines. Results: In multivariate mixed-effects regression, the introduction of the CHW program was associated with a 2.1-point decrease in PHQ-9 score (95% CI: -3.7 to -0.50) followed by a decrease in PHQ-9 score of 0.19 points per month (95% CI: -0.41 to 0.02), beyond standard care. There was strong evidence that patients were far more likely to attend a mean of at least one visit per month (adjusted OR = 8.5, 95% CI: 7.2 to 9.7) after the intervention was introduced in a community. Conclusions: Our results suggest an association between the introduction of a CHW program and improved depression outcomes and appointment adherence. Our findings are limited by missing data. Future research is necessary to develop evidence-based mental health interventions implementable in low-resource settings.
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    A concerted neuron–astrocyte program declines in ageing and schizophrenia
    (Springer Science and Business Media LLC, 2024-03-06) Ling, Emi; Nemesh, James; Goldman, Melissa; Kamitaki, Nolan; Reed, Nora; Handsaker, Robert E.; Genovese, Giulio; Vogelgsang, Jonathan S.; Gerges, Sherif; Meyer, Daniel; Ghosh, Sulagna; Lutservitz, Alyssa; Mullally, Christopher D.; Wysoker, Alec; Kashin, Seva; Spina, Liv; Esposito, John M.; French, Kiely; Neumann, Anna; Hogan, Marina; Ichihara, Kiku; Berretta, Sabina; McCarroll, Steven A.
    Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing—two conditions that involve declines in cognitive flexibility and plasticity —cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.