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Genetics //

Publications

Kowalec K, Fitzgerald KC, Salter A, Dolovich C, Harder A, Bernstein CN, Bolton J, Cutter GR, Graff LA, Hägg S, Hitchon CA, Lu Y, Lublin FD, McKay KA, Patten SB, Patki A, Tiwari HK, Wolinsky JS, Marrie RA. Polygenicity of comorbid depression in multiple sclerosis. Neurology 2023; Aug 1: 101(5): e522-e532.

Depression is common in multiple sclerosis and is associated with faster disability progression. The etiology of comorbid depression in multiple sclerosis remains poorly understood. Identification of individuals with a high risk of depression, through polygenic scores, may facilitate earlier identification. Previous genetic studies of depression considered depression as a primary disorder, not a comorbidity, and thus, findings may not generalize to multiple sclerosis. Body mass index (BMI) is a risk factor of both multiple sclerosis and depression, and its association may highlight differences in depression in multiple sclerosis. To improve the understanding of comorbid depression in multiple sclerosis, we will investigate polygenic scores in people with multiple sclerosis, with the hypothesis that a higher depression polygenic scores is associated with increased odds for comorbid depression in multiple sclerosis. Samples from 3 sources (Canada, UK Biobank, and the United States) were used. Individuals were grouped into cases (multiple sclerosis/comorbid depression) and compared with 3 control groups: multiple sclerosis/no depression, depression/no immune disease, and healthy persons. We used 3 depression definitions: lifetime clinical diagnoses, self-reported diagnoses, and depressive symptoms. The polygenic scores were tested in association with depression using regression. Results: A total of 106,682 individuals of European genetic ancestry were used: Canada (n = 370; 213 with multiple sclerosis), UK Biobank (n = 105,734; 1,390 with multiple sclerosis), and the United States (n = 578 with multiple sclerosis). Meta-analyses revealed individuals with multiple sclerosis and depression had a higher depression polygenic scores compared with both individuals with multiple sclerosis without depression (odds ratio range per SD 1.29-1.38, p < 0.05) and healthy controls (odds ratio range per SD 1.49-1.53, p < 0.025), regardless of the definition applied and when sex stratified. The BMI polygenic scores were associated with depressive symptoms (p ≤ 0.001). The depression polygenic scores did not differ between depression occurring as a comorbid condition with multiple sclerosis or as the primary condition (odds ratio range per SD 1.03-1.13, all p > 0.05). A higher depression genetic burden was associated with approximately 30%-40% increased odds of depression in European genetic ancestry participants with multiple sclerosis compared with those without depression and was no different compared with those with depression and no comorbid immune disease. Conclusions This study paves the way for further investigations into the possible use of polygenic scores for assessing psychiatric disorder risk in multiple sclerosis and its application to non-European genetic ancestries.

Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LM, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabrie SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Iyer IP, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O’Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, PonsioenCY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Daniel L. Rice DL, Saavalainen P, Sand B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, Sheikh SZ, Silverberg M, Simmons A, Skeiceviciene J, Sokol H, Solomonson M, Somineni H, Sun D, Targan S, Turner D, Uhlig HH, van der Meulen AE, Vermeire S, VerstocktS, Voskuil MD, Winter HS, Young J, Duerr RH, Franke A, Brant SR, Cho J, Weersma RK, Parkes M, Xavier RJ, Rivas MA, Rioux JD, McGovern DPB, Huang H, Anderson CA, Daly MJ. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Nature Genetics 2022; 54: 1275-1283.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease. However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with Crohn's disease and 80,000 population controls. We directly implicate ten genes in general onset Crohn's disease for the first time to our knowledge via association to coding variation, four of which lie within established Crohn's disease GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in Crohn's disease cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in Crohn's disease pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

 

Kowalec K, Salter A, Fitzgerald KC, Patel M, Han J, Lu Y, Bolton JM, Hitchon C, Bernstein CN, Patten S, Graff LA, Marriott JJ, Marrie RA, for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Depressive symptom trajectories and polygenic risk scores in individuals with an immune-mediated inflammatory disease. General Hospital Psychiatry 2022; Jul-Aug; 77: 21-28.

To develop group-based trajectories of depressive symptoms in immune-mediated inflammatory disease to understand their evolution and identify any associated factors, with the overall goal of identifying those at highest risk of higher depressive symptom burden. 922 participants had an immune-mediated inflammatory disease or anxiety/depression. The PHQ-9 was administered at four visits, and polygenic risk scores for major depressive disorder, depressive symptoms, and body mass index (BMI) were generated. Group-based trajectory modelling of PHQ-9 scores estimated distinct trajectories. Regression tested whether specific factors were associated with the trajectories. Mediation analyses assessed whether immune-mediated inflammatory disease mediated the association between BMI PRS and trajectories. Results: Three trajectories were identified. Regression demonstrated those in Group 3 ('high symptoms') had significantly higher polygenic risk scores for the three traits, compared to Group 1 ('minimal symptoms') (OR: 1.34-1.66, P < 0.01). Stratified analyses in the immune-mediated inflammatory disease subgroup revealed an increased effect for BMI polygenic risk scores in Group 3 (OR: 2.31, P < 0.001), in contrast, BMI polygenic risk scores was no longer associated in the non- immune-mediated inflammatory disease sample. No significant indirect effect of BMI polygenic risk scores on depressive symptoms trajectories was identified via immune-mediated inflammatory disease. Conclusions: A significant association between polygenicity and PHQ-9 trajectories supports a role for genetic inheritance in the variability in depressive symptoms in immune-mediated inflammatory disease.

 

Li Y, Bernstein CN, Xu W, Hu P. Polygenic risk and causal inference of psychiatric comorbidity in inflammatory bowel disease among patients with European ancestry. Journal of Translational Medicine 2022; in press

 

Approximately 40% of persons with IBD experience psychiatric comorbidities. Previous studies demonstrated the polygenetic effect on both IBD and psychiatric comorbidities. In this study, we evaluated the contribution of genetic variants to psychiatric comorbidities among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of psychiatric comorbidities in persons with IBD.

The polygenic risk score was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated polygenic risk score and psychiatric comorbidities status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated polygenic risk score and psychiatric comorbidities status in IBD.

The estimated polygenic risk score had a significantly positive association with psychiatric comorbidities status (for the highest effect: P-value threshold = 5 × 10-3, odds ratio = 2.0, P-value = 1.5 × 10-5). Around 13% of the causal effect between the polygenic risk score and psychiatric comorbidities status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based psychiatric comorbidities prediction model is around 0.7 at the threshold of 5 × 10-4.

PC status in IBD depends on genetic influences among persons with European ancestry. The polygenic risk score could potentially be applied to psychiatric comorbidities risk screening to identify persons with IBD at a high risk of psychiatric comorbidities. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

Bruinooge A, Liu Q, Tian Y, Jiang W, Li Y, Xu W, Bernstein CN, Hu P. Genetic predictors of gene expression associated with psychiatric comorbidity in patients with inflammatory bowel disease – a pilot study. Genomics 2021 May;113(3):919-932. 

 

IBD affects millions of people in North America, and patients with IBD have a high incidence of psychiatric comorbidities. The genetic mechanisms underlying the link are, in general, poorly understood. A transcriptome-wide association study was performed using genetically regulated gene expression profiles imputed from the genetic profiles of 240 IBD patients in the Manitoba IBD Cohort Study. The imputation was performed using the 44 non-diseased human tissue-specific reference models from the GTEx database. Linear modeling and gene set enrichment analysis were performed to identify genes and pathways that are significantly associated with IBD patients with psychiatric comorbidities compared to IBD alone in each of the 44 non-diseased human tissues. Finally, an enrichment map was generated to investigate networks of the enriched gene sets associated with IBD patients with psychiatric comorbidities. The genes RBPMS in skeletal muscle (adjusted p = 0.05), KCNA5 in the cerebellar hemisphere of the brain (adjusted p = 0.09), GSR, SMIM34A, and LIPT2 in the frontal cortex of the brain (adjusted p = 0.09 for each) were the top genetically regulated genes with a suggestive association with IBD patients with PC. We identified three gene set networks, which include gene sets and pathways with a suggestive association with IBD patients with psychiatric comorbidities: one with 7 gene sets overlapping in apolipoprotein B mRNA editing subunit genes, one with 3 gene sets including pigmentation gene sets, and the other one with 3 gene sets including peptidyl tyrosine phosphorylation regulation related gene sets.

 

We concluded that our transcriptome-wide association study analysis has identified genes and pathways with a suggestive association with IBD patients with psychiatric comorbidities. These findings can be potentially used for illustrating the mechanism of developing psychiatric comorbidities in the patients with IBD and developing diagnosis tool or drug targets for IBD

Samarani S, Mack DR, Bernstein CN, Iannello A, Debbeche O, Jantchou P, Faure C, Deslandres C, Amre DA, Ahmad A. Activating Killer-cell Immunoglobulin-like Receptor genes confer risk for Crohn’s disease in children and adults of the Western European descent: Findings based on case-control studies. PLOS One 2019;14(6):e0217767. Published 2019 Jun 13

Killer-cell Immunoglobulin-like Receptor genes encode receptors, which are mainly expressed on, and control functional activities of, Natural Killer (NK) cells. These cells are important in the inflammatory response. Activated NK cells can potentially cause tissue destruction, which might be important in development Crohn disease. In this study we performed case control studies on three independent Canadian Crohn’s disease patient cohorts (all of Western European descent): two comprising children [one from Montreal (438 children) and one from Ottawa (213 children)] and one comprising predominantly adults (from Winnipeg having 364 adults)]. We assess the gene types for for activating Killer-cell Immunoglobulin-like Receptor. We observed strong associations between all the six Killer-cell Immunoglobulin-like Receptor genes and Crohn’s disease in Ottawa children. The results were mostly replicated in the Montreal cohort of children nd the Winnipeg cohort of adults. Similarly associations between five genes were observed in the adult Winnipeg cohort. An overall analysis for all cohorts showed strong associations with four of the genes, with the strongest association evident for a gene called KIR2DS5. In the combined analysis for four Killer-cell Immunoglobulin-like Receptor genes, individuals carrying one or more of the Killer-cell Immunoglobulin-like Receptor genes were at significantly higher risks for acquiring Crohn’s disease.

We concluded that activating Killer-cell Immunoglobulin-like Receptor genes are associated with risk for developing CD in both children and adults. 

 

Frenkel S, Bernstein CN, Sargent M, Kuang Q, Jiang W, Wei J, Thiruvahindrapuram B, Spriggs E, Scherer SW, Hu P. Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease. PLOS One 2019; 14(6): e0217846. Published 2019 Jun 11.

We hypothesized that rare (<0.1% population frequency) gene copy number variations (CNVs) could play an important mechanism for risk of IBD. We aimed to examine changes in DNA copy number in a population-based cohort of patients with IBD and search for novel genetic risk factors for IBD. DNA samples from 243 individuals with IBD from the Manitoba IBD Cohort Study and 2988 healthy controls were analyzed using genome-wide SNP microarray technology. We identified IBD-associated genes affected by rare CNV from comparing the number of overlapping CNVs in IBD samples with the number of overlapping CNVs in controls for each gene. 4,402 CNVs detected by two or three algorithms intersected 7,061 genes, in at least one analyzed sample. Four genes (e.g. DUSP22 and IP6K3) intersected by rare deletions and fourteen genes (e.g. SLC25A10, PSPN, GTF2F1) intersected by rare duplications demonstrated significant association with IBD (FDR-adjusted p-value < 0.01). Of these, ten genes were functionally related to immune response and intracellular signalling pathways. Some of these genes were also identified in other IBD related genome-wide association studies. These suggested that the identified genes may play a role in the risk of IBD.

Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.

Frenkel S, Bernstein CN, Jin YW, Sargent M, Kuang Q, Jiang W, Wei J, Thiruvahindrapuram B, Scherer SW, Hu P. Genome-wide copy number variant data for inflammatory bowel disease in a Caucasian population. Data in Brief 2019; Jul 2; 25:104203.

 

Genome-wide copy-number association studies offer new opportunities to identify the mechanisms underlying complex diseases, including chronic inflammatory, psychiatric disorders and others. We have used genotyping microarrays to analyse the copy-number variants (CNVs) from 243 Caucasian individuals with inflammatory bowel disease. The CNV data was obtained by using multiple quality control measures and merging the results of three different CNV detection algorithms: PennCNV, iPattern, and QuantiSNP. The final dataset contains 4,402 CNVs detected by two or three algorithms independently with high confidence. This paper provides a detailed description of the data generation and quality control steps. For further interpretation of the data presented in this article, please see the research article entitled Copy number variation-based gene set analysis reveals cytokine signalling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease.

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