Kaarina Kowalec

In Canada, schizophrenia is a mental health condition that can lead to disability and early death. Researchers have used large databases to find genetic factors that contribute to our understanding of how schizophrenia works, however none of these studies included people from Manitoba and very few from Canada. We want to create a Manitoba-specific study to understand schizophrenia, where we will invite people with schizophrenia to participate by providing a blood sample. We will also collect medical data, and link to other data sources that are already available such as that from medical records and or other government sources. This is unlike any other study in Canada, because Manitoba has unique medical data available, where it covers most of a person's life, from birth to the end of life. These large databases that link genetic and medical data for conditions like schizophrenia are uncommon globally, but we also have access to a similar study in Sweden. Accessing this Swedish data can help to compare our findings from Manitoba with an outside country that is like Canada. Our goal is to provide a better understanding of schizophrenia in Canadians, compare with that of the Swedish study, and perform research to understand how genetics play a role in schizophrenia. To achieve these goals, we have three main aims: (1) create the Manitoba Schizophrenia Study, (2) examine if there genetic differences between those with and without schizophrenia, and compare this to individuals from Sweden and (3) investigate whether any genetic factors play a role in antipsychotic drug prescribing. The results from this project will create a highly coveted and novel resource for schizophrenia researchers in Canada, support new knowledge to improve our understanding of schizophrenia and may lead to new insights into the condition and potential targets for better treatments.

Background: This project directly addresses two FY24 MSRP focus areas: (a) identifying correlates of disease progression in MS and (b) understanding mechanisms contributing to MS etiology and disease course. Aging is a key determinant of physical impairment progression in MS, making it crucial to identify an individual's "reserve," which is the capacity to resist or delay such impairments. Brain reserve, represented by intracranial volume (ICV), reflects an individual's neurobiological capital and ability to tolerate MS-related pathology. Physical reserve refers to the ability to resist disease-related physical decline. Unfortunately, the contribution of reserve to MS-related impairments is poorly understood, especially regarding the genetic contributions. This proposal aims to fill this gap by characterizing and evaluating polygenic scores (PGS) – cumulative genetic loads for traits like brain volumes and aging-related diseases – to brain and physical reserve in MS. By using PGS as stable genetic factors from birth, we can identify novel mechanisms and potential therapeutic targets, excluding reverse causation._x000D_ _x000D_ Hypothesis/Objective(s)_x000D_ Specific Aims: We aim to identify whether aging associated PGS are correlates of MS disease progression. Our objectives are to (1) Validate the association between ICV PGS and brain reserve in PwMS, (2) Examine the association between PGS for aging-related traits and brain atrophy in MS and (3) Investigate the link between PGS for physical reserve in MS. We hypothesize that the PGS for ICV will be associated with brain reserve in people with PwMS, as observed in non-MS populations. We also hypothesize that PGS for aging-related traits will be associated with greater physical reserve in PwMS, manifesting as lower physical impairment for a given degree of brain atrophy._x000D_ _x000D_ Study Design: We will utilize five well-characterized cohorts from Canada, USA, Sweden, the UK and the global MS-PATHS network, comprising a total of 1,800-4,900 PwMS. Data will be pooled using random-effect inverse-variance weighted meta-analysis. For Objective 1, we will validate the association of the ICV PGS with head size-normalized ICV using quantile regression, adjusting for covariates such as genetic ancestry, age and sex. For Objective 2, we will construct a generalized linear model to predict physical function (z-score Timed-25-foot walk) based on brain volume, adding each PGS sequentially to determine its contribution to physical reserve._x000D_ _x000D_ Innovation: This research is among the first to assess whether PGS developed in large non-MS populations can predict brain reserve in PwMS. Additionally, by examining the genetic burden of aging-related traits in relation to physical reserve, this study could identify aspects of reserve that are potentially modifiable, offering new insights into MS progression._x000D_ _x000D_ Impact: The proposed research will generate new knowledge about the biological factors influencing reserve and the risk of physical impairments in MS, potentially leading to novel therapeutic targets. Improved understanding of reserve could enhance the ability to identify PwMS at high risk of accelerated physical decline, guiding more personalized and effective use of disease-modifying therapies. This is particularly important as even the most effective therapies currently available do not fully prevent disability progression in MS.

Over 90,000 people have multiple sclerosis (MS) in Canada. Each person's experience with MS is different. These differences are likely caused by a mix of factors. Examples of some of these factors are a person's sex, gender, age, ethnicity, and if they live in a city or not. Together, these factors contribute to a person's diversity. Past MS research has not included people who are very diverse even though some diversity factors can put a person with MS at a disadvantage for their health. Currently, researchers are unsure which diversity factors put people at the greatest health disadvantage. This in turn limits access to the right types of support and care. Our long-term goal is to improve health in people with MS who have not been included in past research. We will take three steps to reach our goal. First, we will develop ways to test how biological factors including genetics, age and sex, contribute to health outcomes in people with MS. Second, we will recruit 500 diverse people with MS to look at how a person's biology, lifetime experiences, and environment impact their health outcomes. We will look at the outcomes of quality of life and ability to live independently. Third, we will find and test ways to best support people with MS who experience health disadvantages because of their experiences and environments. During our work we will involve people with MS, health care providers, advocacy groups, and health care decision makers. Working with a big team will improve our chances that our findings will be meaningful and helpful for people with MS, regardless of what diversity factors they experience.

Reserve is someone’s ability to tolerate age-related changes and disease-related insults to their brain without developing symptoms. How reserve contributes specifically to multiple sclerosis disease is unknown. There are two types of reserve: “Brain reserve” which is like an individual’s “hardware”, and “cognitive reserve” which is your “software”. Whether differences in someone’s DNA contribute to reserve have not been considered. To address this, we seek to understand where DNA or genetic differences play a role in brain and cognitive reserve in multiple sclerosis. Our first goal is to understand factors associated with brain and cognitive reserve in multiple sclerosis that could be used to advance treatment and care. Our second goal is to better understand how multiple genetic differences influence the volume of brain over time. This may help with identifying who with multiple sclerosis may benefit the most from therapeutics.

Neurogenomics, Pharmacogenomics, Precision Medicine Automated preparation of samples for precise genomic analyses