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Krishnan Radhakrishnan

Bio: Krishnan Radhakrishnan is an academic researcher from Substance Abuse and Mental Health Services Administration. The author has contributed to research in topics: Cancer & Prostate cancer. The author has an hindex of 4, co-authored 13 publications receiving 128 citations. Previous affiliations of Krishnan Radhakrishnan include University of Kentucky & VA Boston Healthcare System.

Papers
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Journal ArticleDOI
TL;DR: The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1), which may have implications for genetic vulnerability across several psychiatric disorders.
Abstract: Objective:Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comor...

141 citations

Posted ContentDOI
10 Sep 2019-bioRxiv
TL;DR: The utility of genetics is pointed to to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.
Abstract: Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to re-experiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 – 0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

19 citations

Journal ArticleDOI
TL;DR: The VESsel GENeration (VESGEN) analysis software as discussed by the authors was used for the analysis of 2D vascular trees, networks, and tree-network composites.
Abstract: The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

10 citations

Journal ArticleDOI
TL;DR: In this paper, the authors investigated the genomics of Gulf War Illness (GWI) within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys and genomic data, enabling genome-wide association studies (GWASs).
Abstract: Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

7 citations


Cited by
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08 Nov 2011
TL;DR: ThePHQ-9, GAD-7 and PHQ-15 are brief well-validated measures for detecting and monitoring depression, anxiety and somatization.
Abstract: BACKGROUND Depression, anxiety and somatization are the most common mental disorders in primary care as well as medical specialty populations; each is present in at least 5-10% of patients and frequently comorbid with one another. An efficient means for measuring and monitoring all three conditions would be desirable. METHODS Evidence regarding the psychometric and pragmatic characteristics of the Patient Health Questionnaire (PHQ)-9 depression, generalized anxiety disorder (GAD)-7 anxiety and PHQ-15 somatic symptom scales are synthesized from two sources: (1) four multisite cross-sectional studies (three conducted in primary care and one in obstetric-gynecology practices) comprising 9740 patients, and (2) key studies from the literature that have studied these scales. RESULTS The PHQ-9 and its abbreviated eight-item (PHQ-8) and two-item (PHQ-2) versions have good sensitivity and specificity for detecting depressive disorders. Likewise, the GAD-7 and its abbreviated two-item (GAD-2) version have good operating characteristics for detecting generalized anxiety, panic, social anxiety and post-traumatic stress disorder. The optimal cutpoint is > or = 10 on the parent scales (PHQ-9 and GAD-7) and > or = 3 on the ultra-brief versions (PHQ-2 and GAD-2). The PHQ-15 is equal or superior to other brief measures for assessing somatic symptoms and screening for somatoform disorders. Cutpoints of 5, 10 and 15 represent mild, moderate and severe symptom levels on all three scales. Sensitivity to change is well-established for the PHQ-9 and emerging albeit not yet definitive for the GAD-7 and PHQ-15. CONCLUSIONS The PHQ-9, GAD-7 and PHQ-15 are brief well-validated measures for detecting and monitoring depression, anxiety and somatization.

607 citations

Journal ArticleDOI
TL;DR: To estimate survival based on a competing risk analysis stratified by age at diagnosis and histologic findings for men diagnosed as having clinically localized prostate cancer and who were managed conservatively, a Retrospective cohort study is presented.

337 citations

Journal ArticleDOI
TL;DR: BCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors, which may form the basis of new BCR risk stratification (European Association of Urology BCR Risk Groups), which needs to be validated formally.

241 citations

Journal ArticleDOI
TL;DR: A genetic study of problematic alcohol use in 435,563 individuals, including data from the Million Veteran Program, Psychiatric Genomics Consortium and UK Biobank, found many novel risk loci and provided new insights into trait biology.
Abstract: Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

195 citations

01 Feb 2019
TL;DR: AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.
Abstract: OBJECTIVE: Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits. METHOD: This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank [N=121,604] and 23andMe [N=20,328]) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P). RESULTS: The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76-0.92) and DSM-IV alcohol dependence (rg=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (rg=0.22), major depressive disorder (rg=0.26), and attention deficit hyperactivity disorder (rg=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (rg=-0.24) and ADHD (rg=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (rg=0.82) while retaining most subjects. CONCLUSIONS: AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.

188 citations