Biology subjects

Soumya Raychaudhuri

Publications and source records attributed to Soumya Raychaudhuri.

8 recordsLinked to original sources

bioRxiv2016

Polygenic analysis of schizophrenia and 19 immune diseases reveals modest pleiotropy

Epidemiological studies indicate that many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenotypic correlation between immune diseases and schizophrenia might be explained by shared genetic risk factors (genetic correlation). We used data from a large genome-wide association study (GWAS) of schizophrenia (N=35,476 cases and 46,839 controls) to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified three variants with pleiotropic effects, located in regions associated with both schizophrenia and immune disease. Our analyses provided the strongest evidence of pleiotropy at rs1734907 ([~]85kb upstream of EPHB4), a variant which was associated with increased risk of both Crohns disease (OR = 1.16, P = 1.67x10-13) and schizophrenia (OR = 1.07, P = 7.55x10-6). Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using polygenic risk scores (PRS) and cross-trait LD Score regression (LDSC). PRS revealed significant genetic overlap with schizophrenia for narcolepsy (p=4.1x10-4), primary biliary cirrhosis (p=1.4x10-8), psoriasis (p=3.6x10-5), systemic lupus erythematosus (p=2.2x10-8), and ulcerative colitis (p=4.3x10-4). Genetic correlations between these immune diseases and schizophrenia, estimated using LDSC, ranged from 0.10 to 0.18 and were consistent with the expected phenotypic correlation based on epidemiological data. We also observed suggestive evidence of sex-dependent genetic correlation between schizophrenia and multiple sclerosis (interaction p=0.02), with genetic risk scores for multiple sclerosis associated with greater risk of schizophrenia among males but not females. Our findings suggest that shared genetic risk factors contribute to the epidemiological co-occurrence of schizophrenia and certain immune diseases, and suggest that in some cases this genetic correlation is sex-dependent. Author SummaryImmune diseases occur at different rates among patients with schizophrenia compared to the general population. While the reasons for this phenotypic correlation are unclear, shared genetic risk (genetic correlation) has been proposed as a contributing factor. Prior studies have estimated the genetic correlation between schizophrenia and a handful of immune diseases, with conflicting results. Here, we performed a comprehensive cross-disorder investigation of schizophrenia and 19 immune diseases. We identified three individual genetic variants associated with both schizophrenia and immune diseases, including a variant near EPHB4 - a gene whose protein product guides the migration of lymphocytes towards infected cells in the immune system and the migration of neuronal axons in the brain. We demonstrated significant genome-wide genetic correlation between schizophrenia and narcolepsy, primary biliary cirrhosis, psoriasis, systemic lupus erythematosus, and ulcerative colitis. Finally, we identified a potential sex-dependent pleiotropic effect between schizophrenia and multiple sclerosis. Our findings point to shared genetic risk for schizophrenia and at least a subset of immune diseases, which likely contributes to their epidemiological co-occurrence. These results raise the possibility that the same genetic variants may exert their effects on neurons or immune cells to influence the development of psychiatric and immune disorders, respectively.

Genetics↗

bioRxiv2015

Novel protective associations with age-related macular degeneration: A common variant near CTRB1 and a rare variant in PELI3

Although >20 common frequency age-related macular degeneration (AMD) alleles have been discovered with genome-wide association studies, substantial disease heritability remains unexplained. In this study we sought to identify additional variants, both common and rare, that have an association with advanced AMD. We genotyped 4,332 cases and 25,268 controls of European ancestry from three different populations using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants and performed single variant and gene-based burden tests to identify associations with rare variants. Two protective, low frequency, non-synonymous variants A307V in PELI3 (odds ratio [OR]=0.14, P=4.3x10-10) and N1050Y in CFH (OR=0.76, Pconditional=1.6x10-11) were significantly associated with a decrease in risk of AMD. Additionally, we identified an enrichment of protective alleles in PELI3 using a burden test (OR=0.14). The new variants have a large effect size, similar to rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR=18.82, P=3.5x10-07), C3 K155Q (OR=3.27, P=1.5x10-10), and C9 P167S (OR=2.04, P=2.8x10-07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR = 0.71, P = 1.8x10-07; Firth corrected OR = 0.64, P = 9.6x10-11). This study supports the involvement of both common and low frequency protective variants in AMD. It also may expand the role of the high-density lipoprotein pathway and branches of the innate immune pathway, outside that of the complement system, in the etiology of AMD.

Genetics↗

bioRxiv2015

Using genotype data to distinguish pleiotropy from heterogeneity: deciphering coheritability in autoimmune and neuropsychiatric diseases

Shared genetic architecture between phenotypes may be driven by a common genetic basis (pleiotropy) or a subset of genetically similar individuals (heterogeneity). We developed BUHMBOX, a well-powered statistical method to distinguish pleiotropy from heterogeneity using genotype data. We observed a shared genetic basis between 11 of 17 tested autoimmune diseases and type I diabetes (T1D, p<10-12) and 11 of 17 tested autoimmune diseases and rheumatoid arthritis (RA, p<10-7). This sharing could not be explained by heterogeneity (corrected pBUHMBOX>0.2 using 6,670 T1D cases and 7,279 RA cases), suggesting that shared genetic features in autoimmunity are due to pleiotropy. We observed a shared genetic basis between seronegative and seropostive RA (p<10-22), explained by heterogeneity (pBUHMBOX=0.008 in 2,406 seronegative RA cases). Consistent with previous observations, we observed genetic sharing between major depressive disorder (MDD) and schizophrenia (p<10-9). This sharing is not explained by heterogeneity (pBUHMBOX=0.28 in 9,238 MDD cases).

Genomics↗

bioRxiv2015

Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to five autoimmune diseases

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia, and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to five diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify six immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.

Genetics↗

bioRxiv2015

Tissue-specific Enrichment of Lymphoma Risk Loci in Regulatory Elements

Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non-Hodgkins lymphoma subtype chronic lymphocytic leukemia, are significantly enriched for co-localization with epigenetic marks of active gene regulation. These enrichments were seen in a lymphoid-specific manner for numerous ENCODE datasets, including DNase-hypersensitivity as well as multiple segmentation-defined enhancer regions. Furthermore, we identify putatively functional SNPs that are both in regulatory elements in lymphocytes and are associated with gene expression changes in blood. We developed an algorithm, UES, that uses a Monte Carlo simulation approach to calculate the enrichment of previously identified risk SNPs in various functional elements. This multiscale approach integrating multiple datasets helps disentangle the underlying biology of lymphoma, and more broadly, is generally applicable to GWAS results from other diseases as well.

Genetics↗

bioRxiv2015

Partitioning heritability by functional category using GWAS summary statistics

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

Genetics↗

bioRxiv2014

Disentangling effects of colocalizing genomic annotations to functionally prioritize non-coding variants within complex trait loci

Identifying genomic annotations that differentiate causal from associated variants is critical to fine-map disease loci. While many studies have identified non-coding annotations overlapping disease variants, these annotations colocalize, complicating fine-mapping efforts. We demonstrate that conventional enrichment tests are inflated and cannot distinguish causal effects from colocalizing annotations. We developed a sensitive and specific statistical approach that is able to identify independent effects from colocalizing annotations. We first confirm that gene regulatory variants map to DNase-I hypersensitive sites (DHS) near transcription start sites. We then show that (1) 15-35% of causal variants within disease loci map to DHS independent of other annotations; (2) breast cancer and rheumatoid arthritis loci harbor potentially causal variants near the summits of histone marks rather than full peak bodies; and (3) variants associated with height are highly enriched for embryonic stem cell DHS sites. We highlight specific loci where we can most effectively prioritize causal variation.

Genomics↗

bioRxiv2014

Regulatory variants explain much more heritability than coding variants across 11 common diseases

Common variants implicated by genome-wide association studies (GWAS) of complex diseases are known to be enriched for coding and regulatory variants. We applied methods to partition the heritability explained by genotyped SNPs [Formula] across functional categories (while accounting for shared variance due to linkage disequilibrium) to genotype and imputed data for 11 common diseases. DNaseI Hypersensitivity Sites (DHS) from 218 cell-types, spanning 16% of the genome, explained an average of 79% of [Formula] (5.1x enrichment; P < 10-20); further enrichment was observed at enhancer and cell-type specific DHS elements. The enrichments were much smaller in analyses that did not use imputed data or were restricted to GWAS-associated SNPs. In contrast, coding variants, spanning 1% of the genome, explained only 8% of [Formula] enrichment; P = 5 x 10-4). We replicated these findings but found no significant contribution from rare coding variants in an independent schizophrenia cohort genotyped on GWAS and exome chips.

Genetics↗