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201. Genome-wide screen to identify genetic loci associated with cognitive decline in late-life depression

Author: Karen Soldano, Guy G. Potter, Melanie E. Garrett, Allison E. Ashley-Koch, David C. Steffens, and Douglas R. McQuoid
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, Candidate gene, business.industry, Context (language use), Genome-wide association study, Late life depression, medicine.disease, Article, 03 medical and health sciences, Psychiatry and Mental health, Clinical Psychology, 0302 clinical medicine, Internal medicine, Medicine, Dementia, SNP, Geriatrics and Gerontology, Cognitive decline, business, Gerontology, Neurocognitive, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Objective: This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression. Design: A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. Setting: Longitudinal, naturalistic follow-up study. Participants: Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center. Measurements: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE. Results: The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing (p = 3.7 × 10−7; false discovery rate q = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in SLC27A1 (p = 1.1 × 10−5). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. SLC27A1 is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer’s disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in GRXCR1 (p = 1.1 × 10−6), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing. Conclusions: Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.
Published: 2020
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202. Impact of traumatic life events and polygenic risk scores for major depression and posttraumatic stress disorder on Iraq/Afghanistan Veterans

Author: Rachele K. Lipsky, Melanie E. Garrett, Michelle F. Dennis, Michael A. Hauser, Jean C. Beckham, Allison E. Ashley-Koch, and Nathan A. Kimbrel
Subjects: Psychiatry and Mental health, Biological Psychiatry
Abstract: Traumatic experiences and genetic heritability are among the most widely acknowledged risk factors leading to the development of psychopathology; including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). The purpose of this study was to investigate if polygenic risk scores (PRS) among Veterans interacted with traumatic stress to predict PTSD and MDD. 1,389 Iraq-Afghanistan military service Veterans from the Mental Illness Research Education and Clinical Center dataset were analyzed. Genome-wide association study (GWAS) statistics were utilized to generate PRS for PTSD (PRS
Published: 2022

203. Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program

Author: Xuejun Qin, Daniel Jacobson, Nathan Kimbrel, Allison Ashley-Koch, Ravi Madduri, and Melanie Garrett
Subjects: Cancer Research, Genetics, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract: Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q’sEXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors.
Published: 2023
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204. Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans

Author: Nathan A, Kimbrel, Allison E, Ashley-Koch, Xue J, Qin, Jennifer H, Lindquist, Melanie E, Garrett, Michelle F, Dennis, Lauren P, Hair, Jennifer E, Huffman, Daniel A, Jacobson, Ravi K, Madduri, Jodie A, Trafton, Hilary, Coon, Anna R, Docherty, Niamh, Mullins, Douglas M, Ruderfer, Philip D, Harvey, Benjamin H, McMahon, David W, Oslin, Jean C, Beckham, Elizabeth R, Hauser, Michael A, Hauser, and Robert, Striker
Subjects: Psychiatry and Mental health
Abstract: ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.Main Outcome and MeasuresSITB.ResultsA total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P −8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.Conclusions and RelevanceThe findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.
Published: 2023
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205. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Author: Taub, Margaret A., Conomos, Matthew P., Keener, Rebecca, Iyer, Kruthika R., Weinstock, Joshua S., Yanek, Lisa R., Lane, John, Miller-Fleming, Tyne W., Brody, Jennifer A., Raffield, Laura M., McHugh, Caitlin P., Jain, Deepti, Gogarten, Stephanie M., Laurie, Cecelia A., Keramati, Ali, Arvanitis, Marios, Smith, Albert V., Heavner, Benjamin, Barwick, Lucas, Becker, Lewis C., Bis, Joshua C., Blangero, John, Bleecker, Eugene R., Burchard, Esteban G., Celedón, Juan C., Chang, Yen Pei C., Custer, Brian, Darbar, Dawood, de las Fuentes, Lisa, DeMeo, Dawn L., Freedman, Barry I., Garrett, Melanie E., Gladwin, Mark T., Heckbert, Susan R., Hidalgo, Bertha A., Irvin, Marguerite R., Islam, Talat, Johnson, W. Craig, Kaab, Stefan, Launer, Lenore, Lee, Jiwon, Liu, Simin, Moscati, Arden, North, Kari E., Peyser, Patricia A., Rafaels, Nicholas, Seidman, Christine, Weeks, Daniel E., Wen, Fayun, Wheeler, Marsha M., Williams, L. Keoki, Yang, Ivana V., Zhao, Wei, Aslibekyan, Stella, Auer, Paul L., Bowden, Donald W., Cade, Brian E., Chen, Zhanghua, Cho, Michael H., Cupples, L. Adrienne, Curran, Joanne E., Daya, Michelle, Deka, Ranjan, Eng, Celeste, Fingerlin, Tasha E., Guo, Xiuqing, Hou, Lifang, Hwang, Shih-Jen, Johnsen, Jill M., Kenny, Eimear E., Levin, Albert M., Liu, Chunyu, Minster, Ryan L., Naseri, Take, Nouraie, Mehdi, Reupena, Muagututi‘a Sefuiva, Sabino, Ester C., Smith, Jennifer A., Smith, Nicholas L., Lasky-Su, Jessica, Taylor, James G., VI, Telen, Marilyn J., Tiwari, Hemant K., Tracy, Russell P., White, Marquitta J., Zhang, Yingze, Wiggins, Kerri L., Weiss, Scott T., Vasan, Ramachandran S., Taylor, Kent D., Sinner, Moritz F., Silverman, Edwin K., Shoemaker, M. Benjamin, Sheu, Wayne H.-H., Sciurba, Frank, Schwartz, David A., Rotter, Jerome I., Roden, Daniel, Redline, Susan, Raby, Benjamin A., Psaty, Bruce M., Peralta, Juan M., Palmer, Nicholette D., Nekhai, Sergei, Montgomery, Courtney G., Mitchell, Braxton D., Meyers, Deborah A., McGarvey, Stephen T., Mak, Angel C.Y., Loos, Ruth J.F., Kumar, Rajesh, Kooperberg, Charles, Konkle, Barbara A., Kelly, Shannon, Kardia, Sharon L.R., Kaplan, Robert, He, Jiang, Gui, Hongsheng, Gilliland, Frank D., Gelb, Bruce D., Fornage, Myriam, Ellinor, Patrick T., de Andrade, Mariza, Correa, Adolfo, Chen, Yii-Der Ida, Boerwinkle, Eric, Barnes, Kathleen C., Ashley-Koch, Allison E., Arnett, Donna K., Albert, Christine, Laurie, Cathy C., Abecasis, Goncalo, Nickerson, Deborah A., Wilson, James G., Rich, Stephen S., Levy, Daniel, Ruczinski, Ingo, Aviv, Abraham, Blackwell, Thomas W., Thornton, Timothy, O’Connell, Jeff, Cox, Nancy J., Perry, James A., Armanios, Mary, Battle, Alexis, Pankratz, Nathan, Reiner, Alexander P., and Mathias, Rasika A.
Published: 2022
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206. Genome-wide association study of subcortical brain volume in PTSD cases and trauma-exposed controls

Author: Morey, Rajendra A., Davis, Sarah L., Garrett, Melanie E., Haswell, Courtney C., Mid-Atlantic MIRECC Workgroup, Marx, Christine E., Beckham, Jean C., McCarthy, Gregory, Hauser, Michael A., and Ashley-Koch, Allison E.
Published: 2017
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207. Interactions between genotype and retrospective ADHD symptoms predict lifetime smoking risk in a sample of young adults

Author: McClernon, F. Joseph, Fuemmeler, Bernard F., Kollins, Scott H., Kail, Melanie E., and Ashley-Koch, Allison E.
Published: 2008

208. Clonal hematopoiesis in sickle cell disease

Author: L. Alexander Liggett, Liam D. Cato, Joshua S. Weinstock, Yingze Zhang, S. Mehdi Nouraie, Mark T. Gladwin, Melanie E. Garrett, Allison Ashley-Koch, Marilyn J. Telen, Brian Custer, Shannon Kelly, Carla L. Dinardo, Ester C. Sabino, Paula Loureiro, Anna B. Carneiro-Proietti, Cláudia Maximo, Alexander P. Reiner, Gonçalo R. Abecasis, David A. Williams, Pradeep Natarajan, Alexander G. Bick, and Vijay G. Sankaran
Subjects: Male, Whole Genome Sequencing, Humans, Female, General Medicine, Anemia, Sickle Cell, Clonal Hematopoiesis
Abstract: BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH.
Published: 2021

209. Genome-wide association study and meta-analysis of intraocular pressure

Author: Ozel, A. Bilge, Moroi, Sayoko E., Reed, David M., Nika, Melisa, Schmidt, Caroline M., Akbari, Sara, Scott, Kathleen, Rozsa, Frank, Pawar, Hemant, Musch, David C., Lichter, Paul R., Gaasterland, Doug, Branham, Kari, Gilbert, Jesse, Garnai, Sarah J., Chen, Wei, Othman, Mohammad, Heckenlively, John, Swaroop, Anand, Abecasis, Gonçalo, Friedman, David S., Zack, Don, Ashley-Koch, Allison, Ulmer, Megan, Kang, Jae H., Liu, Yutao, Yaspan, Brian L., Haines, Jonathan, Allingham, R. Rand, Hauser, Michael A., Pasquale, Louis, Wiggs, Janey, Richards, Julia E., Li, Jun Z., and NEIGHBOR Consortium
Published: 2014
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210. Linkage Disequilibrium Inflates Type I Error Rates in Multipoint Linkage Analysis when Parental Genotypes Are Missing

Author: Boyles, Abee L., Scott, William K., Martin, Eden R., Schmidt, Silke, Li, Yi-Ju, Ashley-Koch, Allison, Bass, Meredyth P., Schmidt, Michael, Pericak-Vance, Margaret A., Speer, Marcy C., and Hauser, Elizabeth R.
Published: 2005

211. Correction: In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.

Author: Blair R Anderson, David N Howell, Karen Soldano, Melanie E Garrett, Nicholas Katsanis, Marilyn J Telen, Erica E Davis, and Allison E Ashley-Koch
Subjects: Genetics, QH426-470
Published: 2015
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212. In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.

Author: Blair R Anderson, David N Howell, Karen Soldano, Melanie E Garrett, Nicholas Katsanis, Marilyn J Telen, Erica E Davis, and Allison E Ashley-Koch
Subjects: Genetics, QH426-470
Abstract: African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.
Published: 2015
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213. An examination of the association between 5-HTTLPR, combat exposure, and PTSD diagnosis among U.S. veterans.

Author: Yutao Liu, Melanie E Garrett, Michelle F Dennis, Kimberly T Green, VA Mid-Atlantic MIRECC Registry Workgroup, Allison E Ashley-Koch, Michael A Hauser, Jean C Beckham, and Nathan A Kimbrel
Subjects: Medicine, Science
Abstract: To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans.The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat-exposed veterans. Participants were genotyped for the 5-HTTLPR/rs25531 variants of the SLC6A4 gene. A structured clinical interview was used to diagnose PTSD. Combat and civilian trauma exposure were assessed with validated self-report instruments. Logistic regression was used to test for main effects of 5-HTTLPR on PTSD diagnosis as well as gene x environment (GxE) interactions after adjusting for sex, ancestry proportion scores, civilian trauma exposure, and combat exposure.Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S' allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample. In addition, no evidence for combat x 5-HTTLPR effects were observed in either sample.The present study suggests that there may be an association between 5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found.
Published: 2015
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214. Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veterans Program.

Author: Ashley-Koch, Allison E., Kimbrel, Nathan A., Qin, Xue J., Lindquist, Jennifer H., Garrett, Melanie E., Dennis, Michelle F., Hair, Lauren P., Huffman, Jennifer E., Jacobson, Daniel A., Madduri, Ravi K., Coon, Hilary, Docherty, Anna R., Kang, Jooeun, Mullins, Niamh, Ruderfer, Douglas M., Harvey, Philip D., McMahon, Benjamin H., Oslin, David W., Hauser, Elizabeth R., and Hauser, Michael A.
Subjects: *SUICIDAL ideation, *GENOME-wide association studies, *ATTEMPTED suicide, *LOCUS (Genetics), *SUICIDAL behavior, *DIALECTICAL behavior therapy, *VETERANS
Abstract: Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors. Author summary: Suicidal ideation often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The underlying genetic risk of suicidal ideation in the absence of suicide attempt is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. To find these potential genetic risk variants, we examined blood samples from over 600,000 veterans from Million Veteran Program. Four regions of the genome were significantly associated with risk of suicidal ideation in the absence of suicide attempt across four major ancestral groups (European, African, Hispanic and Asian). Two of those regions on chromosomes 6 and 9, were also significantly associated with suicidal ideation in European ancestry-only veterans, as well as with suicide attempt in an independent sample of mostly civilian individuals. No other genetic regions were identified in other ancestry-only analyses, underscoring the need to increase representation of individuals with diverse ancestry. Suicidal ideation without suicide attempt was genetically correlated with other psychiatric disorders, including suicide attempt, post-traumatic stress disorder and major depressive disorder. Our novel findings suggest that multiple genes contribute to genetic risk for suicidal ideation and that the genetic risk is largely shared with suicide attempt and other psychiatric conditions that frequently co-occur with suicidal ideation. [ABSTRACT FROM AUTHOR]
Published: 2023
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215. Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.

Author: Kimbrel, Nathan A., Ashley-Koch, Allison E., Qin, Xue J., Lindquist, Jennifer H., Garrett, Melanie E., Dennis, Michelle F., Hair, Lauren P., Huffman, Jennifer E., Jacobson, Daniel A., Madduri, Ravi K., Trafton, Jodie A., Coon, Hilary, Docherty, Anna R., Mullins, Niamh, Ruderfer, Douglas M., Harvey, Philip D., McMahon, Benjamin H., Oslin, David W., Beckham, Jean C., and Hauser, Elizabeth R.
Subjects: VETERANS, SUICIDAL ideation, SYNAPSES, SUICIDAL behavior, UNITED States armed forces, CYCLIC adenylic acid
Abstract: Key Points: Question: Is there a genetic basis for suicidal thoughts and behaviors (SITB)? Findings: This genome-wide association study of SITB including 633 778 US military veterans identified 7 genome-wide significant cross-ancestry risk loci through meta-analysis, and top loci were independently replicated in a large international cohort. Meaning: This study identified multiple novel cross-ancestry candidate risk genes for SITB; however, more work is needed to replicate these findings and determine whether these genes might impact clinical care. This genome-wide association study including 633 778 US military veterans evaluates potential genetic risk loci for suicidal thoughts and behaviors among US military veterans. Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. Objective: To identify novel, replicable genomic risk loci for SITB. Design, Setting, and Participants: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022. Main Outcome and Measures: SITB. Results: A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10−8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry. Conclusions and Relevance: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care. [ABSTRACT FROM AUTHOR]
Published: 2023
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216. GENOME-WIDE ASSOCIATION STUDY META-ANALYSIS OF SUICIDE ATTEMPT IN 43,871 CASES IDENTIFIES TWELVE GENOME-WIDE SIGNIFICANT LOCI

Author: Anna Docherty, Niamh Mullins, Allison Ashley-Koch, Andrey Shabalin, Balazs Murnyak, Jooeun Kang, Xuejun Qin, Emily DiBlasi, Hilary Coon, Nate Kimbrel, Jean Beckham, and Douglas Ruderfer
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical), Biological Psychiatry
Published: 2022
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217. IDENTIFICATION OF NOVEL, REPLICABLE GENETIC RISK LOCI FOR SUICIDAL THOUGHTS AND BEHAVIORS WITHIN THE MILLION VETERAN PROGRAM (MVP) COHORT

Author: Nate Kimbrel, Allison Ashley-Koch, Jean Beckham, Beth Hauser, and Mike Hauser
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical), Biological Psychiatry
Published: 2022
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218. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster

Author: Solovieff, Nadia, Milton, Jacqueline N., Hartley, Stephen W., Sherva, Richard, Sebastiani, Paola, Dworkis, Daniel A., Klings, Elizabeth S., Farrer, Lindsay A., Garrett, Melanie E., Ashley-Koch, Allison, Telen, Marilyn J., Fucharoen, Supan, Ha, Shau Yin, Li, Chi-Kong, Chui, David H.K., Baldwin, Clinton T., and Steinberg, Martin H.
Published: 2010
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219. A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci

Author: Nathan A, Kimbrel, Allison E, Ashley-Koch, Xue J, Qin, Jennifer H, Lindquist, Melanie E, Garrett, Michelle F, Dennis, Lauren P, Hair, Jennifer E, Huffman, Daniel A, Jacobson, Ravi K, Madduri, Jodie A, Trafton, Hilary, Coon, Anna R, Docherty, Jooeun, Kang, Niamh, Mullins, Douglas M, Ruderfer, Philip D, Harvey, Benjamin H, McMahon, David W, Oslin, Elizabeth R, Hauser, Michael A, Hauser, and Jean C, Beckham
Subjects: Black or African American, Genetic Loci, Humans, Genetic Predisposition to Disease, Suicide, Attempted, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study, Veterans
Abstract: To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10
Published: 2021

220. Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function

Author: Zhang, Yuankai, Liu, Xue, Wiggins, Kerri L., Kurniansyah, Nuzulul, Guo, Xiuqing, Rodrigue, Amanda L., Zhao, Wei, Yanek, Lisa R., Ratliff, Scott M., Pitsillides, Achilleas, Aguirre Patiño, Juan Sebastian, Sofer, Tamar, Arking, Dan E., Austin, Thomas R., Beiser, Alexa S., Blangero, John, Boerwinkle, Eric, Bressler, Jan, Curran, Joanne E., Hou, Lifang, Hughes, Timothy M., Kardia, Sharon L.R., Launer, Lenore J., Levy, Daniel, Mosley, Thomas H., Nasrallah, Ilya M., Rich, Stephen S., Rotter, Jerome I., Seshadri, Sudha, Tarraf, Wassim, González, Kevin A., Ramachandran, Vasan, Yaffe, Kristine, Nyquist, Paul A., Psaty, Bruce M., DeCarli, Charles S., Smith, Jennifer A., Glahn, David C., González, Hector M., Bis, Joshua C., Fornage, Myriam, Heckbert, Susan R., Fitzpatrick, Annette L., Liu, Chunyu, Satizabal, Claudia L., Aguilera, Norma, Ament, Seth, Ammous, Farah, Arnett, Donna K, Becker, Diane, Bis, Joshua, Blue, Elizabeth, Boerwinkle, Eric, Breaux, Camille, Bressler, Jan, Chaar, Dima, MHI, Clarkson-Townsend, Danielle, Cooper, Brigidann, Coresh, Josef, Correa, Adolfo, DeStefano, Anita, Ding, Jingzhong, Fardo, David, Fitzpatrick, Annette, Fornage, Myriam, French, Jennifer, Glahn, David, Gonzalez, Hector, Granot-Hershkovitz, Einat, Hanly, Patrick, Hayden, Kathleen, Heckbert, Susan, Heemann, Scott, Horvath, Steve, Hoth, Karin, Hughes, Timothy, Jaiswal, Sidd, Jian, Xueqiu, Katsumata, Yuriko, Kho, Minjung, Kooperberg, Charles, Launer, Lenore, Lin, Honghuang, Litkowski, Elizabeth, Longstreth, Will, Martin, Alexandra, Mayeux, Richard, Mikulla, Julie, Miller, Amy, Misra, Biswapriya, Mosley, Thomas, Nyquist, Paul, O'Connell, Jeff, Olivier, Michael, Peloso, Gina, Perry, James, Psaty, Bruce, Purcell, Shaun, Raffield, Laura, Ranaweera, Yugandi, Reiner, Alex, Rotter, Jerome, Sargurupremraj, Muralidharan, Sarnowski, Chloé, Satizabal, Claudia, Schellenberg, Gerard, Schoenbein, Bonnie L, Seshadri, Sudha, Shade, Lincoln, Short, Meghan I, Simino, Jeannette, Smith, Jennifer, Smith, Mallorie, Smoller, Sylvia, Snively, Beverly, Soemedi, Rachel, Sokolow, Sophie, Thorington, Daune, Thornton, Timothy A., Yanek, Lisa, Yang, Qiong, Yu, Miao, Zare, Habil, Zhao, Wei, Abecasis, Goncalo, Abhyankar, Avinash, Aldred, Micheala, Arking, Dan, Ashley-Koch, Allison, Aviv, Abraham, Barnes, Kathleen, Barron-Casella, Emily, Battle, Stephanie, Blackwell, Thomas, Burkardt, Deepika, Castellani, Christina A, Comhair, Suzy, Cooper, Brigidann, Correa, Adolfo, Crockett, Phyllis, de Andrade, Mariza, DeMeo, Dawn, DePaoli, Maria Rizzo, Ding, Jun, Dobski, Christine, Erzurum, Serpil, Farha, Samar, Fetterman, Jessica, Floyd, Caitlin, Fu, Mao, Gist, Amber, Granot-Hershkovitz, Einat, Gu, C. Charles, Heemann, Scott, Hernandez, Ryan, Hong, Yun Soo, Hsu, Yi-Hsiang, Justice, Anne, Lange, Leslie, Levy, Dan, Lin, Honghuang, Liu, Chunyu, Longchamps, Ryan, Ma, Jiantao, Manson, JoAnn, Markus, Tammy, McDonald, Merry-Lynn, McGarvey, Stephen, Mikulla, Julie, Montgomery, Courtney, Musunuri, Rajeeva Lochan, O'Connell, Jeff, Oppong, Richard, Pankratz, Nathan, Qian, Yong, Rotter, Jerome, Shaw, Jessica R, Smith, Albert Vernon, Sofer, Tamar, Streeten, Elizabeth, Tang, Weihong, Taylor, Kent D., Telen, Marilyn, Thompson, Shelby, Thorington, Daune, Tiwari, Hemant, Walsh, Ann, Wan, Emily, Wang, Cuicui, Wang, Heming, Wang, Penglong, Weir, Bruce, Williams, L. Keoki, Wilson, James, Xiao, Shujie, Xu, Weiling, Yang, Yu-Chung, and Zhao, Wei
Published: 2023
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221. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author: Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner
Subjects: Adult, Costa Rica, Male, Pulmonary and Respiratory Medicine, Adolescent, Vital Capacity, Single-nucleotide polymorphism, Pedigree chart, Critical Care and Intensive Care Medicine, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Polymorphism (computer science), Forced Expiratory Volume, Humans, Medicine, SNP, 030212 general & internal medicine, Child, Asthma, Whole Genome Sequencing, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Minor allele frequency, 030228 respiratory system, Genetic epidemiology, Child, Preschool, Interferon Regulatory Factors, Immunology, Respiratory Physiological Phenomena, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules
Abstract: BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
Published: 2019
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222. The TFAP2A–IRF6–GRHL3 genetic pathway is conserved in neurulation

Author: Walid D. Fakhouri, Yunping Lei, Tamara Busch, Simon G. Gregory, Wei Yang, Richard H. Finnell, Arianna L. Smith, Edward Li, Alexander G. Bassuk, Gary M. Shaw, Huiping Zhu, Trevor Williams, Youssef A. Kousa, Tamer A. Mansour, Yang Chai, A. J. Agopian, Laura E. Mitchell, Akira Kinoshita, Brad A. Amendt, Elizabeth J. Leslie, Brian C. Schutte, Eric C. Liao, Xiao Li, Dhruv B. Sharma, Nicole K Patel, Raeuf Roushangar, and Allison E. Ashley-Koch
Subjects: Neural Tube, Exencephaly, Biology, medicine.disease_cause, TFAP2A, Mice, Anencephaly, Genetics, medicine, Animals, Humans, Neural Tube Defects, Neurulation, Spinal Dysraphism, Molecular Biology, Conserved Sequence, Genetics (clinical), Mutation, integumentary system, Neural tube defect, Spina bifida, Neural tube, Gene Expression Regulation, Developmental, General Medicine, medicine.disease, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, Transcription Factor AP-2, Interferon Regulatory Factors, General Article, Signal Transduction, Transcription Factors
Abstract: Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.
Published: 2019
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223. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author: Carly J. van der Heide, Jessica N. Cooke Bailey, Susan Williams, Dan Milea, José Paulo Cabral de Vasconcellos, Sadiq M. Abdullahi, Douglas E. Gaasterland, Ifeoma N. Asimadu, Sayoko E. Moroi, Hasnaa Lamari, Sarah J. Garnai, Janey L. Wiggs, Donald L. Budenz, R. Rand Allingham, Julia E. Richards, Jonathan L. Haines, Jerome I. Rotter, Michael G. Anderson, Xiuqing Guo, Robert M. Feldman, Michael A. Hauser, Yii-Der Ida Chen, Hugo Freire Nunes, Leon W. Herndon, John F. Ervin, Stephen Akafo, Radha Ayyagari, Thomas J. Hoffmann, Rachel W. Kuchtey, Michèle Ramsay, Prisca Biangoup Nyamsi, Zheng Li, Eric Jorgenson, Kar Seng Sim, Ebenezer Obeng-Nyarkoh, William C. Bromley, Christopher A. Girkin, Robert N. Weinreb, Alberta A H J Thiadens, Serge Resnikoff, William E. Sponsel, Maggie C.Y. Ng, Christine M. Hulette, Donald W. Bowden, Saydou Bakayoko, Jeffrey M. Liebmann, Harvey Dubiner, Suhanya Okeke, Abba Hydara, Ruth J. F. Loos, Adeyinka O. Ashaye, Olusegun Olaniyi, Mahmoud B. Alhassan, Khaled K. Abu-Amero, Christopher J Hammond, Tin Aung, John H. Fingert, Robert P. Igo, Shih-Hsiu Wang, Rui Barroso Schimiti, Pratap Challa, Robert F. Mullins, Rodolfo A. Perez-Grossmann, Nouhoum Guirou, Margaret A. Pericak-Vance, Anthony Okeke, Pieter W.M. Bonnemaijer, Paulo Vinicius Svidnicki, Abdoulaye Napo, Louise R. Pasquale, Joyce Kabwe, Chiea Chuen Khor, Mônica Barbosa de Melo, Girish N. Nadkarni, CM Chuka-Okosa, Neil Risch, Nkiru Kizor-Akaraiwe, Miles J. Flamme-Wiese, Cornelia M. van Duijn, N J Uche, Joseph Msosa, Olusola Olawoye, Linda M. Zangwill, Mariana B. Oliveira, Caroline C W Klaver, Allison E. Ashley Koch, Vital Paulino Costa, Ngoy Janvier Kilangalanga, Trevor R. Carmichael, Xue Qin, Kent D. Taylor, Yutao Liu, Dianne A. Cruz, Epidemiology, and Ophthalmology
Subjects: Male, medicine.medical_specialty, Genotype, genetic structures, Open angle glaucoma, Population, Black People, Glaucoma, Genome-wide association study, Polymorphism, Single Nucleotide, 01 natural sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Interquartile range, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, 0101 mathematics, education, Adaptor Proteins, Signal Transducing, Aged, Original Investigation, education.field_of_study, Amyloid beta-Peptides, business.industry, 010102 general mathematics, Case-control study, General Medicine, Odds ratio, Middle Aged, medicine.disease, Immunohistochemistry, eye diseases, Case-Control Studies, Female, Risk assessment, business, Glaucoma, Open-Angle, Genome-Wide Association Study
Abstract: Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
Published: 2019
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224. Influence of the MTHFR C677T Polymorphism on Magnetic Resonance Imaging Hyperintensity Volume and Cognition in Geriatric Depression

Author: Hong, Edmund D., Taylor, Warren D., McQuoid, Douglas R., Potter, Guy G., Payne, Martha E., Ashley-Koch, Allison, and Steffens, David C.
Published: 2009
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225. Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus

Author: Hauser, Michael A., Aboobakar, Inas F., Liu, Yutao, Miura, Shiroh, Whigham, Benjamin T., Challa, Pratap, Wheeler, Joshua, Williams, Andrew, Santiago-Turla, Cecelia, Qin, Xuejun, Rautenbach, Robyn M., Ziskind, Ari, Ramsay, Michèle, Uebe, Steffen, Song, Lingyun, Safi, Alexias, Vithana, Eranga N., Mizoguchi, Takanori, Nakano, Satoko, Kubota, Toshiaki, Hayashi, Ken, Manabe, Shin-ichi, Kazama, Shigeyasu, Mori, Yosai, Miyata, Kazunori, Yoshimura, Nagahisa, Reis, Andre, Crawford, Gregory E., Pasutto, Francesca, Carmichael, Trevor R., Williams, Susan E. I., Ozaki, Mineo, Aung, Tin, Khor, Chiea-Chuen, Stamer, W. Daniel, Ashley-Koch, Allison E., and Allingham, R. Rand
Published: 2015
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226. Evidence for fumonisin inhibition of ceramide synthase in humans consuming maize-based foods and living in high exposure communities in Guatemala

Author: Riley, Ronald T., Torres, Olga, Matute, Jorge, Gregory, Simon G., Ashley-Koch, Allison E., Showker, Jency L., Mitchell, Trevor, Voss, Kenneth A., Maddox, Joyce R., and Gelineau-van Waes, Janee B.
Published: 2015
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227. Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome†

Author: Cope, Heidi, Garrett, Melanie E., Gregory, Simon, and Ashley-Koch, Allison
Published: 2015
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228. A common variant near TGFBR3 is associated with primary open angle glaucoma

Author: Li, Zheng, Allingham, R. Rand, Nakano, Masakazu, Jia, Liyun, Chen, Yuhong, Ikeda, Yoko, Mani, Baskaran, Chen, Li-Jia, Kee, Changwon, Garway-Heath, David F., Sripriya, Sarangapani, Fuse, Nobuo, Abu-Amero, Khaled K., Huang, Chukai, Namburi, Prasanthi, Burdon, Kathryn, Perera, Shamira A., Gharahkhani, Puya, Lin, Ying, Ueno, Morio, Ozaki, Mineo, Mizoguchi, Takanori, Krishnadas, Subbiah Ramasamy, Osman, Essam A., Lee, Mei Chin, Chan, Anita S.Y., Tajudin, Liza-Sharmini A., Do, Tan, Goncalves, Aurelien, Reynier, Pascal, Zhang, Hong, Bourne, Rupert, Goh, David, Broadway, David, Husain, Rahat, Negi, Anil K., Su, Daniel H, Ho, Ching-Lin, Blanco, Augusto Azuara, Leung, Christopher K.S., Wong, Tina T., Yakub, Azhany, Liu, Yutao, Nongpiur, Monisha E., Han, Jong Chul, Hon, Do Nhu, Shantha, Balekudaru, Zhao, Bowen, Sang, Jinghong, Zhang, NiHong, Sato, Ryuichi, Yoshii, Kengo, Panda-Jonas, Songhomita, Ashley Koch, Allison E., Herndon, Leon W., Moroi, Sayoko E., Challa, Pratap, Foo, Jia Nee, Bei, Jin-Xin, Zeng, Yi-Xin, Simmons, Cameron P., Bich Chau, Tran Nguyen, Sharmila, Philomenadin Ferdinamarie, Chew, Merwyn, Lim, Blanche, Tam, Pansy O.S., Chua, Elaine, Ng, Xiao Yu, Yong, Victor H.K., Chong, Yaan Fun, Meah, Wee Yang, Vijayan, Saravanan, Seongsoo, Sohn, Xu, Wang, Teo, Yik Ying, Cooke Bailey, Jessica N., Kang, Jae H., Haines, Jonathan L., Cheng, Ching Yu, Saw, Seang-Mei, Tai, E-Shyong, Richards, Julia E., Ritch, Robert, Gaasterland, Douglas E., Pasquale, Louis R., Liu, Jianjun, Jonas, Jost B., Milea, Dan, George, Ronnie, Al-Obeidan, Saleh A., Mori, Kazuhiko, Macgregor, Stuart, Hewitt, Alex W., Girkin, Christopher A., Zhang, Mingzhi, Sundaresan, Periasamy, Vijaya, Lingam, Mackey, David A., Wong, Tien Yin, Craig, Jamie E., Sun, Xinghuai, Kinoshita, Shigeru, Wiggs, Janey L., Khor, Chiea-Chuen, Yang, Zhenglin, Pang, Chi Pui, Wang, Ningli, Hauser, Michael A., Tashiro, Kei, Aung, Tin, and Vithana, Eranga N.
Published: 2015
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229. Alloimmunization in sickle cell disease: changing antibody specificities and association with chronic pain and decreased survival

Author: Telen, Marilyn J., Afenyi-Annan, Araba, Garrett, Melanie E., Combs, Martha R., Orringer, Eugene P., and Ashley-Koch, Allison E.
Published: 2015
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230. EFFECT OF THE APOE ε4 ALLELE AND COMBAT EXPOSURE ON PTSD AMONG IRAQ/AFGHANISTAN-ERA VETERANS

Author: Kimbrel, Nathan A., Hauser, Michael A., Garrett, Melanie, Ashley-Koch, Allison, Liu, Yutao, Dennis, Michelle F., Klein, Rebecca C., and Beckham, Jean C.
Published: 2015
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231. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.

Author: Megan Ulmer Carnes, Yangfan P Liu, R Rand Allingham, Benjamin T Whigham, Shane Havens, Melanie E Garrett, Chunyan Qiao, NEIGHBORHOOD Consortium Investigators, Nicholas Katsanis, Janey L Wiggs, Louis R Pasquale, Allison Ashley-Koch, Edwin C Oh, and Michael A Hauser
Subjects: Genetics, QH426-470
Abstract: Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.
Published: 2014
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232. Clonal hematopoiesis in sickle cell disease

Author: Liggett La, Melanie E. Garrett, AB Carneiro-Proietti, Mark T. Gladwin, Carla Luana Dinardo, Claudia Maximo, Shannon Kelly, Custer B, Cato Ld, Seyed Mehdi Nouraie, Marilyn J. Telen, G. Abecasis, Alexander P. Reiner, Yingze Zhang, Loureiro P, Joshua S. Weinstock, Pradeep Natarajan, Williams Da, Ester Cerdeira Sabino, Vijay G. Sankaran, Alexander G. Bick, and Allison E. Ashley-Koch
Subjects: Myeloid Malignancy, Myeloid, business.industry, Cancer predisposition, Clonal hematopoiesis, Cell, Disease, Bioinformatics, medicine.anatomical_structure, hemic and lymphatic diseases, Medicine, business, Clone (B-cell biology), Clinical evaluation
Abstract: Curative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. However, the occurrence of several myeloid malignancy cases in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a pre-malignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, no data addressing this issue have been reported. Here, we leverage 74,190 whole-genome sequences to robustly study CH in SCD. While we have sufficient power to detect increased rates of CH, we find no variation in rate or clone properties between individuals affected by SCD and controls. These results should help guide ongoing efforts that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.
Published: 2021
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233. Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

Author: Urbizu, Aintzane, Garrett, Melanie E., Soldano, Karen, Drechsel, Oliver, Loth, Dorothy, Marcé-Grau, Anna, Mestres i Soler, Olga, Poca Pastor, María Antonia, Ossowski, Stephan, Macaya Ruiz, Alfons, Loth, Francis, Labuda, Rick, Ashley-Koch, Allison, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Urbizu A] Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America. Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Garrett ME, Soldano K] Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America. [Drechsel O] Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. Universitat Pompeu Fabra, Barcelona, Spain. [Loth D] Department of Psychology, Conquer Chiari Research Center, University of Akron, Akron, OH, United States of America. [Marcé-Grau A, Macaya A] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Mestres I Soler O] Unitat de Recerca en Neurotraumatologia i Neurocirurgia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Poca MA] Unitat de Recerca en Neurotraumatologia i Neurocirurgia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurocirurgia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Male, Candidate gene, Molecular biology, Epidemiology, Gene Sequencing, Comorbidity, Deformitat d’Arnold-Chiari, Biochemistry, Diagnostic Radiology, 0302 clinical medicine, Sequencing techniques, enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-Chiari [ENFERMEDADES], Medicine and Health Sciences, Coding region, DNA sequencing, Child, Exome sequencing, Chiari malformation, Genetics, Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Radiology and Imaging, Genomics, Phenotype, Magnetic Resonance Imaging, Arnold-Chiari Malformation, Genetic Phenomena::Genetic Variation [PHENOMENA AND PROCESSES], Medicine, Female, Research Article, Adult, Collagen Type VII, Imaging Techniques, Science, Collagen Type VI, Biology, Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari Malformation [DISEASES], Collagen Type I, Neurologia, 03 medical and health sciences, Diagnostic Medicine, fenómenos genéticos::variación genética [FENÓMENOS Y PROCESOS], Exome Sequencing, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, Gene, Alleles, Family Health, Biology and Life Sciences, Proteins, Genetic Variation, Human Genetics, medicine.disease, Research and analysis methods, Genòmica, 030104 developmental biology, Molecular biology techniques, Ehlers–Danlos syndrome, Genetic Loci, Tub neural - Malformacions, Medical Risk Factors, CTD, Collagens, Genètica, 030217 neurology & neurosurgery
Abstract: Seqüenciació de gens; Genòmica; Imatges per ressonància magnètica Secuenciación de genes; Genómica; Imágenes por resonancia magnética Gene sequencing; Genomics; Magnetic resonance imaging Chiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes. This work was supported by a grant from Conquer Chiari to AAK. Collection of the Chiari1000 study participants utilized in this study was supported by a grant from Conquer Chiari to FL at University of Akron. Collection of the Duke study participants utilized in this study was supported by a grant from the National Institutes of Health (NS063273). A.U. was the recipient of a Postdoctoral Fellowship from Fundación Ramón Areces (Spain). RL is the Executive Director of Conquer Chiari which provided some of the funding for this work. For the manuscript, he assisted with revising and editing the manuscript. The funders did have a role in study design, but had no role in data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2021

234. Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

Author: Raluca Gordân, Karen Soldano, Ornit Chiba-Falek, Julio Barrera, Hélène Fradin, Danielle Chipman, Jeffrey Li, Lingyun Song, Julia Gamache, Alexias Safi, Ivana Premasinghe, Daniel Sprague, Melanie E. Garrett, Gregory E. Crawford, Allison E. Ashley-Koch, and Young Yun
Subjects: Male, Apolipoprotein E, snRNA-seq, Datasets as Topic, Gene Expression, ATAC-seq, Late onset, Disease, Neuronal nuclear, Cell Fractionation, Unmet needs, Cellular and Molecular Neuroscience, Alzheimer Disease, Humans, Nuclei sorting, SNP, RC346-429, Molecular Biology, Aged, Gene Library, Aged, 80 and over, Cell Nucleus, Neurons, Sex Characteristics, Chromatin accessibility, Binding Sites, Late-onset Alzheimer’s disease, Base Sequence, biology, RC952-954.6, Middle Aged, Gene dysregulation, Flow Cytometry, Chromatin, Temporal Lobe, Geriatrics, Evolutionary biology, biology.protein, Female, Neurology (clinical), Neurology. Diseases of the nervous system, Single-Cell Analysis, NeuN, Neuroglia, Research Article, Genome-Wide Association Study, Transcription Factors
Abstract: Background In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. Methods We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. Results We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. Conclusions Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Graphical Abstract
Published: 2021
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235. Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Author: Luke Hebert, Karen Soldano, Hope Northrup, Allison E. Ashley-Koch, Do Kyun Kim, Craig Baker, James E. Hixson, Joseph G. Gleeson, Paul Hillman, Alanna C. Morrison, Michael R. Brown, K. S. Au, Sanghee Lee, and Melanie E. Garrett
Subjects: Male, Candidate gene, Meningomyelocele, Science, Diseases, Biology, Bioinformatics, Article, Extracellular matrix, Cell Movement, Developmental biology, Genetics, medicine, Humans, Genetic Predisposition to Disease, Cilia, Neural Tube Defects, Wnt Signaling Pathway, Gene, Cytoskeleton, Genetic Association Studies, Multidisciplinary, Molecular medicine, Cilium, Wnt signaling pathway, Neural tube, Cell migration, Extracellular Matrix, medicine.anatomical_structure, Neurology, Risk factors, Medicine, Female, Gene Deletion, Function (biology), Neuroscience
Abstract: Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.
Published: 2021
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236. Additional file 2 of Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

Author: Barrera, Julio, Song, Lingyun, Gamache, Julia E., Garrett, Melanie E., Safi, Alexias, Yun, Young, Premasinghe, Ivana, Sprague, Daniel, Chipman, Danielle, Li, Jeffrey, Fradin, Hélène, Soldano, Karen, Gordân, Raluca, Ashley-Koch, Allison E., Crawford, Gregory E., and Chiba-Falek, Ornit
Abstract: Additional file 2 : Supplementary Fig. 1: Pearson correlations of all potential numerical covariates and the first ten principal components of the potential numerical covariates. Supplementary Fig. 2. Association of meta variables with case-control status at a Bonferroni significance level of q
Published: 2021
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237. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author: Natarajan, P. (Pradeep), Pampana, A. (Akhil), Graham, S. E. (Sarah E.), Ruotsalainen, S. E. (Sanni E.), Perry, J. A. (James A.), de Vries, P. S. (Paul S.), Broome, J. G. (Jai G.), Pirruccello, J. P. (James P.), Honigbere, M. C. (Michael C.), Aragam, K. (Krishna), Wolford, B. (Brooke), Brody, J. A. (Jennifer A.), Antonacci-Fulton, L. (Lucinda), Arden, M. (Moscati), Aslibekyan, S. (Stella), Assimes, T. L. (Themistocles L.), Ballantyne, C. M. (Christie M.), Bielak, L. F. (Lawrence F.), Bisl, J. C. (Joshua C.), Cade, B. E. (Brian E.), Do, R. (Ron), Doddapaneni, H. (Harsha), Emery, L. S. (Leslie S.), Hung, Y.-J. (Yi-Jen), Irvin, M. R. (Marguerite R.), Khan, A. T. (Alyna T.), Lange, L. (Leslie), Lee, J. (Jiwon), Lemaitre, R. N. (Rozenn N.), Martin, L. W. (Lisa W.), Metcalf, G. (Ginger), Montasser, M. E. (May E.), Moon, J.-Y. (Jee-Young), Muzny, D. (Donna), Connell, J. R. (Jeffrey R. O.), Palmer, N. D. (Nicholette D.), Peralta, J. M. (Juan M.), Peyser, P. A. (Patricia A.), Stilp, A. M. (Adrienne M.), Tsai, M. (Michael), Wang, F. F. (Fei Fei), Weeks, D. E. (Daniel E.), Yanek, L. R. (Lisa R.), Wilson, J. G. (James G.), Abecasis, G. (Goncalo), Arnett, D. K. (Donna K.), Becker, L. C. (Lewis C.), Blangercy, J. (John), Boerwinkle, E. (Eric), Bowden, D. W. (Donald W.), Chang, Y.-C. (Yi-Cheng), Chen, Y. I. (Yii-Der, I), Choi, W. J. (Won Jung), Correa, A. (Adolfo), Curran, J. E. (Joanne E.), Daly, M. J. (Mark J.), DutcherE, S. K. (Susan K.), Ellinor, P. T. (Patrick T.), Fornage, M. (Myriam), Freedman, B. I. (Barry, I), Gabriel, S. (Stacey), Germer, S. (Soren), Gibbs, R. A. (Richard A.), He, J. (Jiang), Hveem, K. (Kristian), Jarvik, G. P. (Gail P.), Kaplan, R. C. (Robert C.), Kardia, S. L. (Sharon L. R.), Kennyn, E. (Eimear), Kim, R. W. (Ryan W.), Kooperberg, C. (Charles), Laurie, C. C. (Cathy C.), Lee, S. (Seonwook), Lloyd-Jones, D. M. (Don M.), Loos, R. J. (Ruth J. F.), Lubitz, S. A. (Steven A.), Mathias, R. A. (Rasika A.), Martinez, K. A. (Karine A. Viaud), McGarvey, S. T. (Stephen T.), Mitche, B. D. (Braxton D.), Nickerson, D. A. (Deborah A.), North, K. E. (Kari E.), Palotie, A. (Aarno), Park, C. J. (Cheol Joo), Psat, B. M. (Bruce M. Y.), Rao, D. C. (D. C.), Redline, S. (Susan), Reiner, A. P. (Alexander P.), Seo, D. (Daekwan), Seo, J.-S. (Jeong-Sun), Smith, A. V. (Albert, V), Tracy, R. P. (Russell P.), Kathiresan, S. (Sekar), Cupples, L. A. (L. Adrienne), Rotten, J. I. (Jerome, I), Morrison, A. C. (Alanna C.), Rich, S. S. (Stephen S.), Ripatti, S. (Samuli), Wilier, C. (Cristen), Peloso, G. M. (Gina M.), Vasan, R. S. (Ramachandran S.), Abe, N. (Namiko), Albert, C. (Christine), Almasy, L. (Laura), Alonso, A. (Alvaro), Ament, S. (Seth), Anderson, P. (Peter), Applebaum-Bowden, D. (Deborah), Arking, D. (Dan), Ashley-Koch, A. (Allison), Auer, P. (Paul), Avramopoulos, D. (Dimitrios), Barnard, J. (John), Barnes, K. (Kathleen), Barr, R. G. (R. Graham), Barron-Casella, E. (Emily), Beaty, T. (Terri), Becker, D. (Diane), Beer, R. (Rebecca), Begum, F. (Ferdouse), Beitelshees, A. (Amber), Benjamin, E. (Emelia), Bezerra, M. (Marcos), Bielak, L. (Larry), Blackwel, T. (Thomas), Bowler, R. (Russell), Broecke, U. (Ulrich), Bunting, K. (Karen), Burchard, E. (Esteban), Buth, E. (Erin), Cardwel, J. (Jonathan), Carty, C. (Cara), Casaburi, R. (Richard), Casella, J. (James), Chaffin, M. (Mark), Chang, C. (Christy), Chasman, D. (Daniel), Chavan, S. (Sameer), Chen, B.-J. (Bo-Juen), Chen, W.-M. (Wei-Min), Chol, M. (Michael), Choi, S. H. (Seung Hoan), Chuang, L.-M. (Lee-Ming), Chung, M. (Mina), Conomos, M. P. (Matthew P.), Cornell, E. (Elaine), Crapo, J. (James), Curtis, J. (Jeffrey), Custer, B. (Brian), Damcott, C. (Coleen), Darbar, D. (Dawood), Das, S. (Sayantan), David, S. (Sean), Davis, C. (Colleen), Daya, M. (Michelle), de Andrade, M. (Mariza), DeBaunuo, M. (Michael), Duan, Q. (Qing), Devine, R. D. (Ranjan Deka Dawn DeMeo Scott), Duggirala, Q. R. (Qing Ravi), Durda, J. P. (Jon Peter), Dutcher, S. (Susan), Eaton, C. (Charles), Ekunwe, L. (Lynette), Farber, C. (Charles), Farnaml, L. (Leanna), Fingerlin, T. (Tasha), Flickinger, M. (Matthew), Franceschini, N. (Nora), Fu, M. (Mao), Fullerton, S. M. (Stephanie M.), Fulton, L. (Lucinda), Gan, W. (Weiniu), Gao, Y. (Yan), Gass, M. (Margery), Ge, B. (Bruce), Geng, X. P. (Xiaoqi Priscilla), Gignoux, C. (Chris), Gladwin, M. (Mark), Glahn, D. (David), Gogarten, S. (Stephanie), Gong, D.-W. (Da-Wei), Goring, H. (Harald), Gu, C. C. (C. Charles), Guan, Y. (Yue), Guo, X. (Xiuqing), Haessler, J. (Jeff), Hall, M. (Michael), Harris, D. (Daniel), Hawle, N. Y. (Nicola Y.), Heavner, B. (Ben), Heckbert, S. (Susan), Hernandez, R. (Ryan), Herrington, D. (David), Hersh, C. (Craig), Hidalgo, B. (Bertha), Hixson, J. (James), Hokanson, J. (John), Hong, E. (Elliott), Hoth, K. (Karin), Hsiung, C. A. (Chao Agnes), Huston, H. (Haley), Hwu, C. M. (Chii Min), Jackson, R. (Rebecca), Jain, D. (Deepti), Jaquish, C. (Cashell), Jhun, M. A. (Min A.), Johnsen, J. (Jill), Johnson, A. (Andrew), Johnson, C. (Craig), Johnston, R. (Rich), Jones, K. (Kimberly), Kang, H. M. (Hyun Min), Kaufman, L. (Laura), Kell, S. Y. (Shannon Y.), Kessler, M. (Michael), Kinney, G. (Greg), Konkle, B. (Barbara), Kramer, H. (Holly), Krauter, S. (Stephanie), Lange, C. (Christoph), Lange, E. (Ethan), Laurie, C. (Cecelia), LeBoff, M. (Meryl), Lee, S. S. (Seunggeun Shawn), Lee, W.-J. (Wen-Jane), LeFaive, J. (Jonathon), Levine, D. (David), Levy, D. (Dan), Lewis, J. (Joshua), Li, Y. (Yun), Lin, H. (Honghuang), Lin, K. H. (Keng Han), Lin, X. (Xihong), Liu, S. (Simin), Liu, Y. (Yongmei), Lunetta, K. (Kathryn), Luo, J. (James), Mahaney, M. (Michael), Make, B. (Barry), Manichaikul, A. (Ani), Mansonl, J. (JoAnn), Margolin, L. (Lauren), Mathai, S. (Susan), McArdle, P. (Patrick), Mcdonald, M.-L. (Merry-Lynn), McFarland, S. (Sean), McHugh, C. (Caitlin), Mei, H. (Hao), Meyers, D. A. (Deborah A.), Mikulla, J. (Julie), Min, N. (Nancy), Minear, M. (Mollie), Minster, R. L. (Ryan L.), Musani, S. (Solomon), Mwasongwe, S. (Stanford), Mychaleckyj, J. C. (Josyf C.), Nadkarni, G. (Girish), Naik, R. (Rakhi), Naseri, T. (Take), Nekhai, S. (Sergei), Nelson, S. C. (Sarah C.), Nickerson, D. (Deborah), Connell, J. O. (Jeff O.), Connor, T. O. (Tim O.), Ochs-Balcom, H. (Heather), Pankow, J. (James), Papanicolaou, G. (George), Parkerl, M. (Margaret), Parsa, A. (Afshin), Penchey, S. (Sara), Perez, M. (Marco), Peters, U. (Ulrike), Phillips, L. S. (Lawrence S.), Phillips, S. (Sam), Pollin, T. (Toni), Post, W. (Wendy), Becker, J. P. (Julia Powers), Boorgula, M. P. (Meher Preethi), Preuss, M. (Michael), Prokopenko, D. (Dmitry), Qasba, P. (Pankaj), Qiao, D. (Dandi), Rafaels, N. (Nicholas), Raffield, L. (Laura), Rasmussen-Torvik, L. (Laura), Ratan, A. (Aakrosh), Reed, R. (Robert), Reganl, E. (Elizabeth), Reupena, M. S. (Muagututi Sefuiva), Rice, K. (Ken), Roden, D. (Dan), Roselli, C. (Carolina), Ruczinski, I. (Ingo), Russel, P. (Pamela), Ruuska, S. (Sarah), Ryan, K. (Kathleen), Sabino, E. C. (Ester Cerdeira), Sakornsakolpatl, P. (Phuwanat), Salzberg, S. (Steven), Sandow, K. (Kevin), Sankaran, V. G. (Vijay G.), Scheller, C. (Christopher), Schmidt, E. (Ellen), Schwander, K. (Karen), Schwartz, D. (David), Sciurba, F. (Frank), Seidman, C. (Christine), Seidman, J. (Jonathan), Sheehan, V. (Vivien), Shetty, A. (Amol), Shetty, A. (Aniket), Sheu, W. H. (Wayne Hui-Heng), Shoemaker, M. B. (M. Benjamin), Silver, B. (Brian), Silvermanl, E. (Edwin), Smith, J. (Jennifer), Smith, J. (Josh), Smith, N. (Nicholas), Smith, T. (Tanja), Smoller, S. (Sylvia), Snively, B. (Beverly), Soferlm, T. (Tamar), Streeten, E. (Elizabeth), Su, J. L. (Jessica Lasky), Sung, Y. J. (Yun Ju), Sylvia, J. (Jody), Sztalryd, C. (Carole), Taliun, D. (Daniel), Tang, H. (Hua), Taub, M. (Margaret), Taylor, K. D. (Kent D.), Taylor, S. (Simeon), Telen, M. (Marilyn), Thornton, T. A. (Timothy A.), Tinker, L. (Lesley), Tirschwel, D. (David), Tiwari, H. (Hemant), Vaidya, D. (Dhananjay), VandeHaar, P. (Peter), Vrieze, S. (Scott), Walker, T. (Tarik), Wallace, R. (Robert), Waits, A. (Avram), Wan, E. (Emily), Wang, H. (Heming), Watson, K. (Karol), Weir, B. (Bruce), Weiss, S. (Scott), Weng, L.-C. (Lu-Chen), Williams, K. (Kayleen), Williams, L. K. (L. Keoki), Wilson, C. (Carla), Wong, Q. (Quenna), Xu, H. (Huichun), Yang, I. (Ivana), Yang, R. (Rongze), Zaghlou, N. (Norann), Zekavat, M. (Maryam), Zhang, Y. (Yingze), Zhao, S. X. (Snow Xueyan), Zhao, W. (Wei), Zni, D. (Degui), Zhou, X. (Xiang), Zhu, X. (Xiaofeng), Zody, M. (Michael), Zoellner, S. (Sebastian), Daly, M. (Mark), Jacob, H. (Howard), Matakidou, A. (Athena), Runz, H. (Heiko), John, S. (Sally), Plenge, R. (Robert), McCarthy, M. (Mark), Hunkapiller, J. (Julie), Ehm, M. (Meg), Waterworth, D. (Dawn), Fox, C. (Caroline), Malarstig, A. (Anders), Klinger, K. (Kathy), Call, K. (Kathy), Mkel, T. (Tomi), Kaprio, J. (Jaakko), Virolainen, P. (Petri), Pulkki, K. (Kari), Kilpi, T. (Terhi), Perola, M. (Markus), Partanen, J. (Jukka), Pitkranta, A. (Anne), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Savinainen, K. (Kimmo), Kosma, V.-M. (Veli-Matti), Kujala, U. (Urho), Tuovila, O. (Outi), Hendolin, M. (Minna), Pakkanen, R. (Raimo), Waring, J. (Jeff), Riley-Gillis, B. (Bridget), Liu, J. (Jimmy), Biswas, S. (Shameek), Diogo, D. (Dorothee), Marshall, C. (Catherine), Hu, X. (Xinli), Gossel, M. (Matthias), Schleutker, J. (Johanna), Arvas, M. (Mikko), Hinttala, R. (Reetta), Kettunen, J. (Johannes), Laaksonen, R. (Reijo), Mannermaa, A. (Arto), Paloneva, J. (Juha), Soininen, H. (Hilkka), Julkunen, V. (Valtteri), Remes, A. (Anne), Klviinen, R. (Reetta), Hiltunen, M. (Mikko), Peltola, J. (Jukka), Tienari, P. (Pentti), Rinne, J. (Juha), Ziemann, A. (Adam), Waring, J. (Jeffrey), Esmaeeli, S. (Sahar), Smaoui, N. (Nizar), Lehtonen, A. (Anne), Eaton, S. (Susan), Landenper, S. (Sanni), Michon, J. (John), Kerchner, G. (Geoff), Bowers, N. (Natalie), Teng, E. (Edmond), Eicher, J. (John), Mehta, V. (Vinay), Gormle, P. Y. (Padhraig Y.), Linden, K. (Kari), Whelan, C. (Christopher), Xu, F. (Fanli), Pulford, D. (David), Frkkil, M. (Martti), Pikkarainen, S. (Sampsa), Jussila, A. (Airi), Blomster, T. (Timo), Kiviniemi, M. (Mikko), Voutilainen, M. (Markku), Georgantas, B. (Bob), Heap, G. (Graham), Rahimov, F. (Fedik), Usiskin, K. (Keith), Maranville, J. (Joseph), Lu, T. (Tim), Oh, D. (Danny), Kalpala, K. (Kirsi), Miller, M. (Melissa), McCarthy, L. (Linda), Eklund, K. (Kari), Palomki, A. (Antti), Isomki, P. (Pia), Piri, L. (Laura), Kaipiainen-Seppnen, O. (Oili), Lertratanaku, A. (Apinya), Bing, D. C. (David Close Marla Hochfeld Nan), Gordillo, J. E. (Jorge Esparza), Mars, N. (Nina), Laitinen, T. (Tarja), Pelkonen, M. (Margit), Kauppi, P. (Paula), Kankaanranta, H. (Hannu), Harju, T. (Terttu), Greenberg, S. (Steven), Chen, H. (Hubert), Betts, J. (Jo), Ghosh, S. (Soumitra), Salomaa, V. (Veikko), Niiranen, T. (Teemu), Juonala, M. (Markus), Metsrinne, K. (Kaj), Khnen, M. (Mika), Junttila, J. (Juhani), Laakso, M. (Markku), Pihlajamki, J. (Jussi), Sinisalo, J. (Juha), Taskinen, M.-R. (Marja-Riitta), Tuomi, T. (Tiinamaija), Laukkanen, J. (Jari), Challis, B. (Ben), Peterson, A. (Andrew), Chu, A. (Audrey), Parkkinen, J. (Jaakko), Muslin, A. (Anthony), Joensuu, H. (Heikki), Meretoja, T. (Tuomo), Aaltonen, L. (Lauri), Auranen, A. (Annika), Karihtala, P. (Peeter), Kauppila, S. (Saila), Auvinen, P. (Pivi), Elenius, K. (Klaus), Popovic, R. (Relja), Schutzman, J. (Jennifer), Loboda, A. (Andrey), Chhibber, A. (Aparna), Lehtonen, H. (Heli), McDonough, S. (Stefan), Crohns, M. (Marika), Kulkarni, D. (Diptee), Kaarniranta, K. (Kai), Turunen, J. (Joni), Ollila, T. (Terhi), Seitsonen, S. (Sanna), Uusitalo, H. (Hannu), Aaltonen, V. (Vesa), Uusitalo-Jrvinen, H. (Hannele), Luodonp, M. (Marja), Hautala, N. (Nina), Strauss, E. (Erich), Chen, H. (Hao), Podgornaia, A. (Anna), Hoffman, J. (Joshua), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Hannula-Jouppi, K. (Katariina), Salmi, T. (Teea), Peltonen, S. (Sirkku), Koulu, L. (Leena), Harvima, I. (Ilkka), Wu, Y. (Ying), Choy, D. (David), Jalanko, A. (Anu), Kajanne, R. (Risto), Lyhs, U. (Ulrike), Kaunisto, M. (Mari), Davis, J. W. (Justin Wade), Quarless, D. (Danjuma), Petrovski, S. (Slav), Chen, C.-Y. (Chia-Yen), Bronson, P. (Paola), Yang, R. (Robert), Chang, D. (Diana), Bhangale, T. (Tushar), Holzinger, E. (Emily), Wang, X. (Xulong), Chen, X. (Xing), Auro, K. (Kirsi), Wang, C. (Clarence), Xu, E. (Ethan), Auge, F. (Franck), Chatelain, C. (Clement), Kurki, M. (Mitja), Karjalainen, J. (Juha), Havulinna, A. (Aki), Palin, K. (Kimmo), Palta, P. (Priit), Parolo, P. D. (Pietro Della Briotta), Zhou, W. (Wei), Lemmel, S. (Susanna), Rivas, M. (Manuel), Harju, J. (Jarmo), Lehisto, A. (Arto), Ganna, A. (Andrea), Llorens, V. (Vincent), Karlsson, A. (Antti), Kristiansson, K. (Kati), Hyvrinen, K. (Kati), Ritari, J. (Jarmo), Wahlfors, T. (Tiina), Koskinen, M. (Miika), Pylkäs, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Mantere, T. (Tuomo), Kangasniemi, E. (Eeva), Heikkinen, S. (Sami), Laakkonen, E. (Eija), Kononen, J. (Juha), Loukola, A. (Anu), Laiho, P. (Pivi), Sistonen, T. (Tuuli), Kaiharju, E. (Essi), Laukkanen, M. (Markku), Jrvensivu, E. (Elina), Lhteenmki, S. (Sini), Mnnikk, L. (Lotta), Wong, R. (Regis), Mattsson, H. (Hannele), Hiekkalinna, T. (Tero), Jimnez, M. G. (Manuel Gonzlez), Donner, K. (Kati), Prn, K. (KaIle), Nunez-Fontarnau, J. (Javier), Kilpelinen, E. (Elina), Sipi, T. P. (Timo P.), Brein, G. (Georg), Dada, A. (Alexander), Awaisa, G. (Ghazal), Shcherban, A. (Anastasia), Sipil, T. (Tuomas), Laivuori, H. (Hannele), Kiiskinen, T. (Tuomo), Siirtola, H. (Harri), Tabuenca, J. G. (Javier Gracia), Kallio, L. (Lila), Soini, S. (Sirpa), Pitknen, K. (Kimmo), and Kuopio, T. (Teijo)
Subjects: Cardiovascular genetics, Genome-wide association studies
Abstract: Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
Published: 2021

238. Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder

Author: Garrett, Melanie E., Qin, Xue Jun, Mehta, Divya, Dennis, Michelle F., Marx, Christine E., Grant, Gerald A., Stein, Murray B., Kimbrel, Nathan A., Beckham, Jean C., Hauser, Michael A., Ashley-Koch, Allison E., other, and, Voisey, Joanne, Garrett, Melanie E., Qin, Xue Jun, Mehta, Divya, Dennis, Michelle F., Marx, Christine E., Grant, Gerald A., Stein, Murray B., Kimbrel, Nathan A., Beckham, Jean C., Hauser, Michael A., Ashley-Koch, Allison E., other, and, and Voisey, Joanne
Abstract: Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common
Published: 2021

239. Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume.

Author: Zheng, Y, Garrett, ME, Sun, D, Clarke-Rubright, EK, Haswell, CC, Maihofer, AX, Elman, JA, Franz, CE, Lyons, MJ, Kremen, WS, Peverill, M, Sambrook, K, McLaughlin, KA, Davenport, ND, Disner, S, Sponheim, SR, Andrew, E, Korgaonkar, M, Bryant, R, Varkevisser, T, Geuze, E, Coleman, J, Beckham, JC, Kimbrel, NA, Sullivan, D, Miller, M, Hayes, J, Verfaellie, M, Wolf, E, Salat, D, Spielberg, JM, Milberg, W, McGlinchey, R, Dennis, EL, Thompson, PM, Medland, S, Jahanshad, N, Nievergelt, CM, Ashley-Koch, AE, Logue, MW, Morey, RA, Zheng, Y, Garrett, ME, Sun, D, Clarke-Rubright, EK, Haswell, CC, Maihofer, AX, Elman, JA, Franz, CE, Lyons, MJ, Kremen, WS, Peverill, M, Sambrook, K, McLaughlin, KA, Davenport, ND, Disner, S, Sponheim, SR, Andrew, E, Korgaonkar, M, Bryant, R, Varkevisser, T, Geuze, E, Coleman, J, Beckham, JC, Kimbrel, NA, Sullivan, D, Miller, M, Hayes, J, Verfaellie, M, Wolf, E, Salat, D, Spielberg, JM, Milberg, W, McGlinchey, R, Dennis, EL, Thompson, PM, Medland, S, Jahanshad, N, Nievergelt, CM, Ashley-Koch, AE, Logue, MW, and Morey, RA
Abstract: The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10-20), thalamus (p = 7.46 × 10-10), caudate (p = 1.97 × 10-18), putamen (p = 1.7 × 10-12), and nucleus accumbens (p = 1.99 × 10-7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = -0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10-19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10-7) or PTSD (rs10861272; p = 1.78 × 10-6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.
Published: 2021

240. Rare and de novo coding variants in chromodomain genes in Chiari I malformation

Author: Sadler, B., Wilborn, J., Antunes, L., Kuensting, T., Hale, A. T., Gannon, S. R., Mccall, K., Cruchaga, C., Harms, M., Voisin, N., Reymond, A., Cappuccio, G., Burnetti-Pierri, N., Tartaglia, M., Niceta, M., Leoni, Chiara, Zampino, Giuseppe, Ashley-Koch, A., Urbizu, A., Garrett, M. E., Soldano, K., Macaya, A., Conrad, D., Strahle, J., Dobbs, M. B., Turner, T. N., Shannon, C. N., Brockmeyer, D., Limbrick, D. D., Gurnett, C. A., Haller, G., Leoni C., Zampino G. (ORCID:0000-0003-3865-3253), Sadler, B., Wilborn, J., Antunes, L., Kuensting, T., Hale, A. T., Gannon, S. R., Mccall, K., Cruchaga, C., Harms, M., Voisin, N., Reymond, A., Cappuccio, G., Burnetti-Pierri, N., Tartaglia, M., Niceta, M., Leoni, Chiara, Zampino, Giuseppe, Ashley-Koch, A., Urbizu, A., Garrett, M. E., Soldano, K., Macaya, A., Conrad, D., Strahle, J., Dobbs, M. B., Turner, T. N., Shannon, C. N., Brockmeyer, D., Limbrick, D. D., Gurnett, C. A., Haller, G., Leoni C., and Zampino G. (ORCID:0000-0003-3865-3253)
Abstract: Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10−10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10−10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10−6). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10−9), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.
Published: 2021

241. Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume

Author: MGGZ, Brain, Zheng, Yuanchao, Garrett, Melanie E, Sun, Delin, Clarke-Rubright, Emily K, Haswell, Courtney C, Maihofer, Adam X, Elman, Jeremy A, Franz, Carol E, Lyons, Michael J, Kremen, William S, Peverill, Matthew, Sambrook, Kelly, McLaughlin, Katie A, Davenport, Nicholas D, Disner, Seth, Sponheim, Scott R, Andrew, Elpiniki, Korgaonkar, Mayuresh, Bryant, Richard, Varkevisser, Tim, Geuze, Elbert, Coleman, Jonathan, Beckham, Jean C, Kimbrel, Nathan A, Sullivan, Danielle, Miller, Mark, Hayes, Jasmeet, Verfaellie, Mieke, Wolf, Erika, Salat, David, Spielberg, Jeffrey M, Milberg, William, McGlinchey, Regina, Dennis, Emily L, Thompson, Paul M, Medland, Sarah, Jahanshad, Neda, Nievergelt, Caroline M, Ashley-Koch, Allison E, Logue, Mark W, Morey, Rajendra A, MGGZ, Brain, Zheng, Yuanchao, Garrett, Melanie E, Sun, Delin, Clarke-Rubright, Emily K, Haswell, Courtney C, Maihofer, Adam X, Elman, Jeremy A, Franz, Carol E, Lyons, Michael J, Kremen, William S, Peverill, Matthew, Sambrook, Kelly, McLaughlin, Katie A, Davenport, Nicholas D, Disner, Seth, Sponheim, Scott R, Andrew, Elpiniki, Korgaonkar, Mayuresh, Bryant, Richard, Varkevisser, Tim, Geuze, Elbert, Coleman, Jonathan, Beckham, Jean C, Kimbrel, Nathan A, Sullivan, Danielle, Miller, Mark, Hayes, Jasmeet, Verfaellie, Mieke, Wolf, Erika, Salat, David, Spielberg, Jeffrey M, Milberg, William, McGlinchey, Regina, Dennis, Emily L, Thompson, Paul M, Medland, Sarah, Jahanshad, Neda, Nievergelt, Caroline M, Ashley-Koch, Allison E, Logue, Mark W, and Morey, Rajendra A
Published: 2021

242. Associations between Epigenetic Age Acceleration and Psychoneurological Symptoms in Sickle Cell Disease

Author: Masese, Rita V, Ashley-Koch, Allison E, Lê, Brandon M, Hatch, Daniel, Yang, Qing, Luyster, Faith, Tanabe, Paula Jean, Shah, Nirmish, and Knisely, Mitchell
Published: 2023
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243. HPA axis function in male caregivers: Effect of the monoamine oxidase-A gene promoter (MAOA-uVNTR)

Author: Brummett, Beverly H., Boyle, Stephen H., Siegler, Ilene C., Kuhn, Cynthia M., Surwit, Richard S., Garrett, Melanie E., Collins, Ann, Ashley-Koch, Allison, and Williams, Redford B.
Published: 2008
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244. BDNF Val66Met genotype and 6-month remission rates in late-life depression

Author: Taylor, W D, McQuoid, D R, Ashley-Koch, A, MacFall, J R, Bridgers, J, Krishnan, R R, and Steffens, D C
Published: 2011
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245. Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease

Author: Ashley-Koch, Allison E., Elliott, Laine, Kail, Melanie E., De Castro, Laura M., Jonassaint, Jude, Jackson, Terry L., Price, Jennifer, Ataga, Kenneth I., Levesque, Marc C., Weinberg, J. Brice, Orringer, Eugene P., Collins, Ann, Vance, Jeffery M., and Telen, Marilyn J.
Published: 2008
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246. Angiotensin receptor gene polymorphisms and 2-year change in hyperintense lesion volume in men

Author: Taylor, W D, Steffens, D C, Ashley-Koch, A, Payne, M E, MacFall, J R, Potocky, C F, and Krishnan, K R R
Published: 2010
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247. Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity

Author: Smith, Taylor F., Anastopoulos, Arthur D., Garrett, Melanie E., Arias-Vasquez, Alejandro, Franke, Barbara, Oades, Robert D., Sonuga-Barke, Edmund, Asherson, Philip, Gill, Michael, Buitelaar, Jan K., Sergeant, Joseph A., Kollins, Scott H., Faraone, Stephen V., and Ashley-Koch, Allison
Published: 2014
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248. No association between RORA polymorphisms and PTSD in two independent samples

Author: Guffanti, G, Ashley-Koch, A E, Roberts, A L, Garrett, M E, Solovieff, N, Ratanatharathorn, A, De Vivo, I, Dennis, M, Ranu, H, Smoller, J W, Liu, Y, Purcell, S M, Beckham, J, Hauser, M A, and Koenen, K C
Published: 2014
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249. Urinary fumonisin B1 and estimated fumonisin intake in women from high- and low-exposure communities in Guatemala

Author: Torres, Olga, Matute, Jorge, Gelineau-van Waes, Janee, Maddox, Joyce R., Gregory, Simon G., Ashley-Koch, Allison E., Showker, Jency L., Zitomer, Nicholas C., Voss, Kenneth A., and Riley, Ronald T.
Published: 2014
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250. Hepatic Gene Expression Profiles Differentiate Presymptomatic Patients With Mild Versus Severe Nonalcoholic Fatty Liver Disease

Author: Moylan, Cynthia A., Pang, Herbert, Dellinger, Andrew, Suzuki, Ayako, Garrett, Melanie E., Guy, Cynthia D., Murphy, Susan K., Ashley-Koch, Allison E., Choi, Steve S., Michelotti, Gregory A., Hampton, Daniel D., Chen, Yuping, Tillmann, Hans L., Hauser, Michael A., Abdelmalek, Manal F., and Diehl, Anna Mae
Published: 2014
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