Publications by authors named "Alicia Martin"

63 Publications

Primary versus secondary nature of mesenteric neuroendocrine tumours.

BMJ Case Rep 2021 Feb 4;14(2). Epub 2021 Feb 4.

Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando, Florida, USA

Neuroendocrine tumours (NETs) are rare group of malignancy that originate from neuroendocrine cells present throughout the body. Most patients with NET first present with symptoms associated with metastasis, and up to 20% of patients have unknown primary site of tumour. Most common metastatic sites for small intestine NETs (SI-NETs) are the locoregional lymph nodes and liver. Although mesenteric metastasis through direct extension or lymphatic spread from SI-NETs is common, mesenteric extranodal involvement is extremely rare, and its biology and primary versus secondary nature are not well understood. Due to their small size and location, SI-NETs are frequently undetected on anatomical imaging or indium-111-pentetreotide single-photon emission computed tomography/CT (Octreoscan) and are difficult to be found via endoscopy. Gallium-68-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-octreotate positron emission tomography (Ga-DOTATATE PET)/CT has been increasingly used for accurate staging, unknown primary tumour site localisation and appropriate management planning. We present a case of an incidentally found mesenteric NET with occult SI-NETs localised preoperatively by Ga-DOTATATE PET/CT.
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http://dx.doi.org/10.1136/bcr-2020-239217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868254PMC
February 2021

Five patients with disorders of calcium metabolism presented with GCM2 gene variants.

Sci Rep 2021 Feb 3;11(1):2968. Epub 2021 Feb 3.

Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Endocrinology and Nutrition Department, Hospital Universitario Cruces, University of the Basque Country (UPV/EHU), Bizkaia, Spain.

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.
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http://dx.doi.org/10.1038/s41598-021-82661-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859196PMC
February 2021

Publisher Correction: Clinical use of current polygenic risk scores may exacerbate health disparities.

Nat Genet 2021 Jan 28. Epub 2021 Jan 28.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41588-021-00797-zDOI Listing
January 2021

Tractor uses local ancestry to enable the inclusion of admixed individuals in GWAS and to boost power.

Nat Genet 2021 02 18;53(2):195-204. Epub 2021 Jan 18.

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African-European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants.
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http://dx.doi.org/10.1038/s41588-020-00766-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867648PMC
February 2021

Molecular Differences Based on Erythrocyte Fatty Acid Profile to Personalize Dietary Strategies between Adults and Children with Obesity.

Metabolites 2021 Jan 8;11(1). Epub 2021 Jan 8.

AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio-Bizkaia, Spain.

As the obesity epidemic continues to grow inexorably worldwide, the need to develop effective strategies to prevent and control obesity seems crucial. The use of molecular tools can be useful to characterize different obesity phenotypes to provide more precise nutritional recommendations. This study aimed to determine the fatty acid (FA) profile of red blood cell (RBC) membranes, together with the evaluation of their dietary intake and biochemical parameters, of children and adults with obesity. An observational study was carried out on 196 children (113 with normal weight and 83 with obesity) and 91 adults (30 with normal weight and 61 with obesity). Mature RBC membrane phospholipids were analyzed for FA composition by gas chromatography-mass spectrometry (GC-MS). Dietary habits were evaluated using validated food frequency questionnaires (FFQ). Children with obesity presented higher levels of ω-6 polyunsaturated FAs (mainly linoleic acid, = 0.01) and lower values of ω-3 FAs (mainly DHA, < 0.001) compared with adults. Regarding blood biochemical parameters, children with obesity presented lower levels of glucose, LDL cholesterol, and alanine aminotransferase compared with adults with obesity. These lipidomic differences could be considered to provide specific nutritional recommendations for different age groups, based on an adequate fat intake.
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http://dx.doi.org/10.3390/metabo11010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827034PMC
January 2021

Pharmacological management of post-traumatic stress disorder and its associated nightmares: A survey of psychiatrists.

J Clin Pharm Ther 2021 Feb 7;46(1):158-165. Epub 2020 Oct 7.

Discipline of Pharmacy, Faculty of Health, University of Canberra, Bruce, Canberra, ACT, Australia.

What Is Known And Objective: To describe the pharmacological management of post-traumatic stress disorder (PTSD) by psychiatrists, with a focus on their use of clinical guidelines and the role of prazosin for nightmares.

Methods: An online survey of Australian and New Zealand psychiatrists was conducted. Aspects included respondent demographics, familiarity and usage of guidelines for PTSD, and opinions on the safety and efficacy of prazosin for PTSD-associated nightmares.

Results And Discussion: A total of 157 responses were recorded, 106 of which were complete. The most frequently used guideline for PTSD management was over 10 years old and used by only 48% of respondents. Peer-reviewed scientific journals were the most common additional source used by psychiatrists to inform their practice. For the targeted treatment of nightmares, 35 different medications had been trialled by respondents. Prazosin had been prescribed by 86% of psychiatrists for PTSD-associated nightmares, with only 2% reporting it to be ineffective in reducing nightmare frequency and/or intensity. Psychiatrists who were familiar with prazosin-mentioning guidelines (P < .05) and those who more frequently treat patients with PTSD (P < .01) were most likely to have prescribed prazosin.

What Is New And Conclusion: Psychiatrists generally do not rely on guidelines to inform the treatment of PTSD. Off-label prescription of prazosin for PTSD-associated nightmares occurs frequently, with positive perceived outcomes, despite conflicting published evidence and a lack of local guideline recommendations for its use.
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http://dx.doi.org/10.1111/jcpt.13274DOI Listing
February 2021

Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx.

Genome Biol 2020 09 11;21(1):233. Epub 2020 Sep 11.

Department of Genetics, Stanford University, Stanford, CA, USA.

Background: Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization.

Results: Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up.

Conclusions: We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.
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http://dx.doi.org/10.1186/s13059-020-02113-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488497PMC
September 2020

Factors involved in prolapse recurrence one year after anterior vaginal repair.

Int Urogynecol J 2020 10 5;31(10):2027-2034. Epub 2020 Aug 5.

Servicio de Obstetricia y Ginecología, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain.

Introduction And Hypothesis: The aim of this study was to identify which factors are associated with anatomic and symptomatic prolapse recurrence in the anterior compartment 1 year after traditional anterior vaginal repair. Our study hypothesis was that major defects in pelvic floor support structures before surgery are associated with higher recurrence rates.

Methods: This was a prospective multicenter study including women with symptomatic anterior compartment prolapse who underwent primary vaginal surgery. Prolapse examination was performed using the Pelvic Organ Prolapse Quantification (POP-Q) system, prolapse symptoms were described using the Pelvic Floor Distress Inventory short form (PFDI-20), and levator ani avulsion and hiatal area were identified by translabial 3D ultrasonography.

Results: During the inclusion period, 455 patients were recruited and 442 (97.1%) attended the 1-year follow-up. In three cases, ultrasound data were not available, and the remaining 439 formed the study group. Anatomic and symptomatic recurrence rates were 45.1% and 6.8%, respectively. Levator avulsion increased the risk of anatomic (OR: 1.96) and symptomatic (OR: 2.60) recurrence; abnormal distensibility of the levator hiatal area increased the risk of anatomic (OR: 2.51) and symptomatic (OR: 2.43) recurrence; advanced prolapse increased the risk of anatomic recurrence: POP-Q stage 3 (OR: 2.34) and POP-Q stage 4 (OR: 5.47).

Conclusions: Major defects in pelvic floor support structures before surgery are associated with higher recurrence rates 1 year after native tissue vaginal repair. Advanced stage of prolapse increases the risk of anatomic recurrence, while levator avulsion and abnormal distensibility of the levator hiatus area increase the risk of both anatomic and symptomatic recurrence.
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http://dx.doi.org/10.1007/s00192-020-04468-1DOI Listing
October 2020

Implementation of a Multidisciplinary Allied Health Optimisation Clinic for Cancer Patients with Complex Needs.

J Clin Med 2020 Jul 30;9(8). Epub 2020 Jul 30.

Department of Allied Health, Peter MacCallum Cancer Centre, Parkville, Victoria 3000, Australia.

This study examined the feasibility of implementing a multidisciplinary allied health model of care (MOC) for cancer patients with complex needs. The MOC in this retrospective study provided up to eight weeks of nutritional counselling, exercise prescription, fatigue management and psychological support. Implementation outcomes (acceptability, adoption, fidelity and appropriateness) were evaluated using nine patient interviews, and operational data and medical records of 185 patients referred between August 2017 and December 2018. Adoption, including intention to try and uptake, were acceptable: 88% of referred patients agreed to screening and 71% of eligible patients agreed to clinic participation. Fidelity was mixed, secondary to inpatient admissions and disease progression interrupting patient participation. Clinician compliance with outcome assessment was variable at program commencement (dietetic, 95%; physiotherapy, 91%; occupational therapy, 33%; quality of life, 23%) and low at program completion (dietetic, 32%; physiotherapy, 13%; occupational therapy, 10%; quality of life, 11%) mainly due to non-attendance. Patient interviews revealed high satisfaction and perceived appropriateness. Adoption of the optimisation clinic was acceptable. Interview responses suggest patients feel the clinic is both acceptable and appropriate. This indicates a multidisciplinary model is an important aspect of comprehensive, timely and effective care. However, fidelity was low, secondary to the complexities of the patient cohort.
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http://dx.doi.org/10.3390/jcm9082431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465605PMC
July 2020

Gender balance in pharmacy leadership: Are we making progress?

Res Social Adm Pharm 2020 May 31. Epub 2020 May 31.

Discipline of Pharmacy, Faculty of Health, University of Canberra, Bruce, Canberra, ACT, 2607, Australia; School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.

Background: In recent years there has been an increasing focus on gender balance and equity in leadership positions. In most fields of work, including female dominated professions such as pharmacy, there is an underrepresentation of women in leadership positions. This is despite significant benefits being observed in organisations when diversity in leadership is increased. To date, there has been no research investigating gender balance in pharmacy leadership and decision-making positions in Australia.

Objective: To explore gender balance in pharmacy leadership in Australia and how it has changed over the last 20 years.

Setting: This study was conducted in Australia.

Method: Eight key Australian pharmacy organisations were identified. Data were extracted from their websites or through direct contact with the organisation for the gender breakdown of their boards/committees/councils from the years 1998-2018.

Results: In total, data were obtained for 368 separate professional committees, from seven organisations (including 22 state/territory branches), covering the years of 1998-2018. Some organisations provided information for each of the 21 years, while others were only able to provide a few data points. Overall, gender balance in pharmacy organisations has increased over the 21-year period however, there remains a lack of women in leadership positions, particularly in the most senior positions where women held only 24% of president/chair positions over the time period. In 2018 women held 34% of these positions, despite representing 62% of pharmacists in Australia.

Conclusion: Gender inequity in leadership is prevalent in the Australian pharmacy profession, although it has lessened over time. Based on the trend from 1998 to 2018 it is predicted that women will achieve an average of 50% representation in Australian pharmacy professional committees no sooner than 2029.
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http://dx.doi.org/10.1016/j.sapharm.2020.05.031DOI Listing
May 2020

Relationship between brain-derived neurotrophic factor and immune function during dietary supplement treatment of elderly with Alzheimer's dementia.

J Clin Transl Res 2020 Jan 29;5(2):68-75. Epub 2020 Jan 29.

Department of Psychiatry and Behavioral Sciences, Miami, Florida.

Background And Aim: The objective of the present study was to investigate the relationships among pro-brain-derived neurotrophic factor (BDNF) and mature BDNF and immune functioning during aloe polymannose multinutrient complex (APMC) treatment in persons with moderate to severe Alzheimer's dementia (AD).

Materials And Methods: An open-label trial of 12 months was used to execute the study. Thirty-four adults with AD were enrolled and consumed four teaspoons/day of APMC for 12 months. Subjects were assessed at baseline and 12 months follow-up for proBDNF and BDNF and cytokines, growth factors, T-cell and B-cell subsets, and complete blood count to measure immune functioning. All biomarkers were intercorrelated.

Results: Several relationships were identified between proBDNF, BDNF, and BDNF/proBDNF ratio and immune function at 12 months, particularly BDNF with vascular endothelial growth factor (VEGF) (=0.55, =0.03), epidermal growth factor (EGF) (=0.74, =0.001), and CD95+CD3+ (%) (=-0.64, =0.03) and proBDNF with VEGF (=0.64, =0.02), EGF (=0.86, <0.001), and CD16+56+ (%) (=-0.78, <0.01). Other correlations were noted for various immune function variables with BDNF, proBDNF, and/or BDNF/proBDNF ratio at baseline and 12 months. Dichotomizing subjects on BDNF above and below 5000 pg/mL revealed additional relationships with platelets and neutrophils.

Conclusions: The associations between BDNF and proBDNF and various immune markers, such as VEGF, EGF, and CD95+CD3+ ratio, provide insight into the link between neurological function and the immune system. These relationships were even stronger in response to APMC treatment, which lends support to previous findings showing improved immune function after dietary supplementation.

Relevance For Patients: AD patients have conventional treatment options with limited efficacy for counteracting the deleterious effects of the disease on neurological function. The link between neurological and immune function has been understudied in this population. Overall, our results showed a significant beneficial relationship between immune and neurological function, particularly in response to 12 months of treatment with an all-natural polysaccharide-based dietary supplement that is a known immunomodulator. Thus, the use of this dietary supplement may benefit these patients by simultaneously improving immune and neurological function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197050PMC
January 2020

Population Histories of the United States Revealed through Fine-Scale Migration and Haplotype Analysis.

Am J Hum Genet 2020 03;106(3):371-388

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

The population of the United States is shaped by centuries of migration, isolation, growth, and admixture between ancestors of global origins. Here, we assemble a comprehensive view of recent population history by studying the ancestry and population structure of more than 32,000 individuals in the US using genetic, ancestral birth origin, and geographic data from the National Geographic Genographic Project. We identify migration routes and barriers that reflect historical demographic events. We also uncover the spatial patterns of relatedness in subpopulations through the combination of haplotype clustering, ancestral birth origin analysis, and local ancestry inference. Examples of these patterns include substantial substructure and heterogeneity in Hispanics/Latinos, isolation-by-distance in African Americans, elevated levels of relatedness and homozygosity in Asian immigrants, and fine-scale structure in European descents. Taken together, our results provide detailed insights into the genetic structure and demographic history of the diverse US population.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058830PMC
March 2020

Population History and Gene Divergence in Native Mexicans Inferred from 76 Human Exomes.

Mol Biol Evol 2020 04;37(4):994-1006

National Laboratory of Genomics for Biodiversity (LANGEBIO), UGA, CINVESTAV, Irapuato, Guanajuato 36821, Mexico.

Native American genetic variation remains underrepresented in most catalogs of human genome sequencing data. Previous genotyping efforts have revealed that Mexico's Indigenous population is highly differentiated and substructured, thus potentially harboring higher proportions of private genetic variants of functional and biomedical relevance. Here we have targeted the coding fraction of the genome and characterized its full site frequency spectrum by sequencing 76 exomes from five Indigenous populations across Mexico. Using diffusion approximations, we modeled the demographic history of Indigenous populations from Mexico with northern and southern ethnic groups splitting 7.2 KYA and subsequently diverging locally 6.5 and 5.7 KYA, respectively. Selection scans for positive selection revealed BCL2L13 and KBTBD8 genes as potential candidates for adaptive evolution in Rarámuris and Triquis, respectively. BCL2L13 is highly expressed in skeletal muscle and could be related to physical endurance, a well-known phenotype of the northern Mexico Rarámuri. The KBTBD8 gene has been associated with idiopathic short stature and we found it to be highly differentiated in Triqui, a southern Indigenous group from Oaxaca whose height is extremely low compared to other Native populations.
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http://dx.doi.org/10.1093/molbev/msz282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086176PMC
April 2020

Comparative genetic architectures of schizophrenia in East Asian and European populations.

Nat Genet 2019 12 18;51(12):1670-1678. Epub 2019 Nov 18.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
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http://dx.doi.org/10.1038/s41588-019-0512-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885121PMC
December 2019

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Cell 2019 10 10;179(3):589-603. Epub 2019 Oct 10.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
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http://dx.doi.org/10.1016/j.cell.2019.08.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939869PMC
October 2019

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Authors:
Caroline M Nievergelt Adam X Maihofer Torsten Klengel Elizabeth G Atkinson Chia-Yen Chen Karmel W Choi Jonathan R I Coleman Shareefa Dalvie Laramie E Duncan Joel Gelernter Daniel F Levey Mark W Logue Renato Polimanti Allison C Provost Andrew Ratanatharathorn Murray B Stein Katy Torres Allison E Aiello Lynn M Almli Ananda B Amstadter Søren B Andersen Ole A Andreassen Paul A Arbisi Allison E Ashley-Koch S Bryn Austin Esmina Avdibegovic Dragan Babić Marie Bækvad-Hansen Dewleen G Baker Jean C Beckham Laura J Bierut Jonathan I Bisson Marco P Boks Elizabeth A Bolger Anders D Børglum Bekh Bradley Megan Brashear Gerome Breen Richard A Bryant Angela C Bustamante Jonas Bybjerg-Grauholm Joseph R Calabrese José M Caldas-de-Almeida Anders M Dale Mark J Daly Nikolaos P Daskalakis Jürgen Deckert Douglas L Delahanty Michelle F Dennis Seth G Disner Katharina Domschke Alma Dzubur-Kulenovic Christopher R Erbes Alexandra Evans Lindsay A Farrer Norah C Feeny Janine D Flory David Forbes Carol E Franz Sandro Galea Melanie E Garrett Bizu Gelaye Elbert Geuze Charles Gillespie Aferdita Goci Uka Scott D Gordon Guia Guffanti Rasha Hammamieh Supriya Harnal Michael A Hauser Andrew C Heath Sian M J Hemmings David Michael Hougaard Miro Jakovljevic Marti Jett Eric Otto Johnson Ian Jones Tanja Jovanovic Xue-Jun Qin Angela G Junglen Karen-Inge Karstoft Milissa L Kaufman Ronald C Kessler Alaptagin Khan Nathan A Kimbrel Anthony P King Nastassja Koen Henry R Kranzler William S Kremen Bruce R Lawford Lauren A M Lebois Catrin E Lewis Sarah D Linnstaedt Adriana Lori Bozo Lugonja Jurjen J Luykx Michael J Lyons Jessica Maples-Keller Charles Marmar Alicia R Martin Nicholas G Martin Douglas Maurer Matig R Mavissakalian Alexander McFarlane Regina E McGlinchey Katie A McLaughlin Samuel A McLean Sarah McLeay Divya Mehta William P Milberg Mark W Miller Rajendra A Morey Charles Phillip Morris Ole Mors Preben B Mortensen Benjamin M Neale Elliot C Nelson Merete Nordentoft Sonya B Norman Meaghan O'Donnell Holly K Orcutt Matthew S Panizzon Edward S Peters Alan L Peterson Matthew Peverill Robert H Pietrzak Melissa A Polusny John P Rice Stephan Ripke Victoria B Risbrough Andrea L Roberts Alex O Rothbaum Barbara O Rothbaum Peter Roy-Byrne Ken Ruggiero Ariane Rung Bart P F Rutten Nancy L Saccone Sixto E Sanchez Dick Schijven Soraya Seedat Antonia V Seligowski Julia S Seng Christina M Sheerin Derrick Silove Alicia K Smith Jordan W Smoller Scott R Sponheim Dan J Stein Jennifer S Stevens Jennifer A Sumner Martin H Teicher Wesley K Thompson Edward Trapido Monica Uddin Robert J Ursano Leigh Luella van den Heuvel Miranda Van Hooff Eric Vermetten Christiaan H Vinkers Joanne Voisey Yunpeng Wang Zhewu Wang Thomas Werge Michelle A Williams Douglas E Williamson Sherry Winternitz Christiane Wolf Erika J Wolf Jonathan D Wolff Rachel Yehuda Ross McD Young Keith A Young Hongyu Zhao Lori A Zoellner Israel Liberzon Kerry J Ressler Magali Haas Karestan C Koenen

Nat Commun 2019 10 8;10(1):4558. Epub 2019 Oct 8.

Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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http://dx.doi.org/10.1038/s41467-019-12576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783435PMC
October 2019

Geographic Variation and Bias in the Polygenic Scores of Complex Diseases and Traits in Finland.

Am J Hum Genet 2019 06 30;104(6):1169-1181. Epub 2019 May 30.

Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki 00014, Finland; Department of Public Health, University of Helsinki, Helsinki 00014, Finland; Helsinki Institute for Information Technology and Department of Mathematics and Statistics, University of Helsinki, Helsinki 00014, Finland. Electronic address:

Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562021PMC
June 2019

Clinical use of current polygenic risk scores may exacerbate health disparities.

Nat Genet 2019 04 29;51(4):584-591. Epub 2019 Mar 29.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation of PRS is that those available today are several times more accurate in individuals of European ancestry than other ancestries. This disparity is an inescapable consequence of Eurocentric biases in genome-wide association studies, thus highlighting that-unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations-clinical uses of PRS today would systematically afford greater improvement for European-descent populations. Early diversifying efforts show promise in leveling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.
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http://dx.doi.org/10.1038/s41588-019-0379-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563838PMC
April 2019

Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies.

Elife 2019 03 21;8. Epub 2019 Mar 21.

Department of Biomedical Informatics, Harvard Medical School, Boston, United States.

Genetic predictions of height differ among human populations and these differences have been interpreted as evidence of polygenic adaptation. These differences were first detected using SNPs genome-wide significantly associated with height, and shown to grow stronger when large numbers of sub-significant SNPs were included, leading to excitement about the prospect of analyzing large fractions of the genome to detect polygenic adaptation for multiple traits. Previous studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the analyses in the UK Biobank, a much more homogeneously designed study. We show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population stratification. More generally, our results imply that typical constructions of polygenic scores are sensitive to population stratification and that population-level differences should be interpreted with caution.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.39702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428571PMC
March 2019

Identification of common genetic risk variants for autism spectrum disorder.

Nat Genet 2019 03 25;51(3):431-444. Epub 2019 Feb 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
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http://dx.doi.org/10.1038/s41588-019-0344-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454898PMC
March 2019

Neuropsychiatric Genetics of African Populations-Psychosis (NeuroGAP-Psychosis): a case-control study protocol and GWAS in Ethiopia, Kenya, South Africa and Uganda.

BMJ Open 2019 02 19;9(2):e025469. Epub 2019 Feb 19.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Introduction: Schizophrenia and bipolar disorder account for a large proportion of the global burden of disease. Despite their enormous impact, little is known about their pathophysiology. Given the high heritability of schizophrenia and bipolar disorder, unbiased genetic studies offer the opportunity to gain insight into their neurobiology. However, advances in understanding the genetic architecture of schizophrenia and bipolar disorder have been based almost exclusively on subjects of Northern European ancestry. The Neuropsychiatric Genetics of African Populations-Psychosis (NeuroGAP-Psychosis) project aims to expand our understanding of the causes of schizophrenia and bipolar disorder through large-scale sample collection and analyses in understudied African populations.

Methods And Analysis: NeuroGAP-Psychosis is a case-control study of 34 000 participants recruited across multiple sites within Ethiopia, Kenya, South Africa and Uganda. Participants will include individuals who are at least 18 years old with a clinical diagnosis of schizophrenia or bipolar disorder ('psychosis') or those with no history of psychosis. Research assistants will collect phenotype data and saliva for DNA extraction. Data on mental disorders, history of physical health problems, substance use and history of past traumatic events will be collected from all participants.DNA extraction will take place in-country, with genotyping performed at the Broad Institute. The primary analyses will include identifying major groups of participants with similar ancestry using the computation-efficient programme single nucleotide polymorphisms (SNP) weights. This will be followed by a GWAS within and across ancestry groups.

Ethics And Dissemination: All participants will be assessed for capacity to consent using the University of California, San Diego Brief Assessment of Capacity to Consent. Those demonstrating capacity to consent will be required to provide informed consent. Ethical clearances to conduct this study have been obtained from all participating sites. Findings from this study will be disseminated in publications and shared with controlled access public databases, such as the database of Genotypes and Phenotypes, dbGaP.
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http://dx.doi.org/10.1136/bmjopen-2018-025469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377543PMC
February 2019

Predicting Polygenic Risk of Psychiatric Disorders.

Biol Psychiatry 2019 07 28;86(2):97-109. Epub 2018 Dec 28.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Genetics provides two major opportunities for understanding human disease-as a transformative line of etiological inquiry and as a biomarker for heritable diseases. In psychiatry, biomarkers are very much needed for both research and treatment, given the heterogenous populations identified by current phenomenologically based diagnostic systems. To date, however, useful and valid biomarkers have been scant owing to the inaccessibility and complexity of human brain tissue and consequent lack of insight into disease mechanisms. Genetic biomarkers are therefore especially promising for psychiatric disorders. Genome-wide association studies of common diseases have matured over the last decade, generating the knowledge base for increasingly informative individual-level genetic risk prediction. In this review, we discuss fundamental concepts involved in computing genetic risk with current methods, strengths and weaknesses of various approaches, assessments of utility, and applications to various psychiatric disorders and related traits. Although genetic risk prediction has become increasingly straightforward to apply and common in published studies, there are important pitfalls to avoid. At present, the clinical utility of genetic risk prediction is still low; however, there is significant promise for future clinical applications as the ancestral diversity and sample sizes of genome-wide association studies increase. We discuss emerging data and methods aimed at improving the value of genetic risk prediction for disentangling disease mechanisms and stratifying subjects for epidemiological and clinical studies. For all applications, it is absolutely critical that polygenic risk prediction is applied with appropriate methodology and control for confounding to avoid repeating some mistakes of the candidate gene era.
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http://dx.doi.org/10.1016/j.biopsych.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599546PMC
July 2019

Effects of Hepatic Ischemia-Reperfusion Injuries and NRF2 on Transcriptional Activities of Bile Transporters in Rats.

J Surg Res 2019 03 24;235:73-82. Epub 2018 Oct 24.

Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Background: The effect of hepatic ischemia-reperfusion injury (IRI) on bile transporter (BT) gene expression is unknown. We hypothesized that abnormal expression of BTs during hepatic IRI is dependent on nuclear factor erythroid 2-related factor 2 (NRF2), which contributes to the cholestasis after reperfusion.

Methods: Sham surgery and short (60 min) or long (90 min) periods of warm ischemia time (WIT) with or without reperfusion for 24 h were applied to wild-type Sprague-Dawley rats and Nrf2 knockout rats (n = 5 per group). At each stage of IRI, the serum levels of aminotransferase, total bilirubin, and bile acids were measured. In addition, hepatic tissue was sampled to determine the histologic score of IRI (Suzuki score), measure adenosine triphosphate (ATP), and identify the quantitative real-time polymerase chain reactions of BTs (Oatp1, Ntcp, Mrp2, Bsep, and Mrp3).

Results: In short periods of WIT, BT expression increased during the ischemia stage and returned to the baseline after reperfusion. However, in long periods of WIT, BT expression did not increase after ischemia and decreased further after reperfusion. Short WIT did not increase BT expression in Nrf2 knockout animals. The level of BT expression was correlated with the Suzuki score, the serum levels of aminotransferase, bilirubin, and bile acids, and tissue ATP level. Stepwise multiple regression analysis derived equations to predict the Suzuki score (R = 76.8, P < 0.001), serum total bilirubin (R = 61.2, P < 0.001), and tissue ATP (R = 61.1, P < 0.001).

Conclusions: Short WIT induces the transcriptional activities of BT, whereas long WIT depresses them, and the effect was blunted by Nrf2 knockout status. BT expression can be considered a surrogate marker for hepatic IRI.
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http://dx.doi.org/10.1016/j.jss.2018.09.057DOI Listing
March 2019

Rapid evolution of a skin-lightening allele in southern African KhoeSan.

Proc Natl Acad Sci U S A 2018 12 10;115(52):13324-13329. Epub 2018 Dec 10.

Department of Ecology and Evolution, State University of New York at Stony Brook, Stony Brook, NY 11794;

Skin pigmentation is under strong directional selection in northern European and Asian populations. The indigenous KhoeSan populations of far southern Africa have lighter skin than other sub-Saharan African populations, potentially reflecting local adaptation to a region of Africa with reduced UV radiation. Here, we demonstrate that a canonical Eurasian skin pigmentation gene, , was introduced to southern Africa via recent migration and experienced strong adaptive evolution in the KhoeSan. To reconstruct the evolution of skin pigmentation, we collected phenotypes from over 400 ≠Khomani San and Nama individuals and high-throughput sequenced candidate pigmentation genes. The derived causal allele in , p.Ala111Thr, significantly lightens basal skin pigmentation in the KhoeSan and explains 8 to 15% of phenotypic variance in these populations. The frequency of this allele (33 to 53%) is far greater than expected from colonial period European gene flow; however, the most common derived haplotype is identical among European, eastern African, and KhoeSan individuals. Using four-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 y ago via a back-to-Africa migration and then experienced a selective sweep (s = 0.04 to 0.05 in ≠Khomani and Nama). The locus is both a rare example of intense, ongoing adaptation in very recent human history, as well as an adaptive gene flow at a pigmentation locus in humans.
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http://dx.doi.org/10.1073/pnas.1801948115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310813PMC
December 2018

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Nat Genet 2019 01 26;51(1):63-75. Epub 2018 Nov 26.

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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http://dx.doi.org/10.1038/s41588-018-0269-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481311PMC
January 2019

Shades of complexity: New perspectives on the evolution and genetic architecture of human skin.

Am J Phys Anthropol 2019 01 8;168 Suppl 67:4-26. Epub 2018 Nov 8.

Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania.

Like many highly variable human traits, more than a dozen genes are known to contribute to the full range of skin color. However, the historical bias in favor of genetic studies in European and European-derived populations has blinded us to the magnitude of pigmentation's complexity. As deliberate efforts are being made to better characterize diverse global populations and new sequencing technologies, better measurement tools, functional assessments, predictive modeling, and ancient DNA analyses become more widely accessible, we are beginning to appreciate how limited our understanding of the genetic bases of human skin color have been. Novel variants in genes not previously linked to pigmentation have been identified and evidence is mounting that there are hundreds more variants yet to be found. Even for genes that have been exhaustively characterized in European populations like MC1R, OCA2, and SLC24A5, research in previously understudied groups is leading to a new appreciation of the degree to which genetic diversity, epistatic interactions, pleiotropy, admixture, global and local adaptation, and cultural practices operate in population-specific ways to shape the genetic architecture of skin color. Furthermore, we are coming to terms with how factors like tanning response and barrier function may also have influenced selection on skin throughout human history. By examining how our knowledge of pigmentation genetics has shifted in the last decade, we can better appreciate how far we have come in understanding human diversity and the still long road ahead for understanding many complex human traits.
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http://dx.doi.org/10.1002/ajpa.23737DOI Listing
January 2019

The critical needs and challenges for genetic architecture studies in Africa.

Curr Opin Genet Dev 2018 12 18;53:113-120. Epub 2018 Sep 18.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date. Additionally, African investigators need to be meaningfully included, as greater inclusivity and enhanced research capacity afford enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages, challenges, and examples of genetic architecture studies of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.
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http://dx.doi.org/10.1016/j.gde.2018.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494470PMC
December 2018

Imputation-Aware Tag SNP Selection To Improve Power for Large-Scale, Multi-ethnic Association Studies.

G3 (Bethesda) 2018 10 3;8(10):3255-3267. Epub 2018 Oct 3.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029

The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. These strategies have benefited from improvements in imputation methods and association tests, however little attention has been paid to ways in which array design can increase rare variant association power. Therefore, we developed a novel framework to select tag SNPs using the reference panel of 26 populations from Phase 3 of the 1000 Genomes Project. We evaluate tag SNP performance mean imputed r at untyped sites using leave-one-out internal validation and standard imputation methods, rather than pairwise linkage disequilibrium. Moving beyond pairwise metrics allows us to account for haplotype diversity across the genome for improve imputation accuracy and demonstrates population-specific biases from pairwise estimates. We also examine array design strategies that contrast multi-ethnic cohorts single populations, and show a boost in performance for the former can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Using our framework, we demonstrate increased imputation accuracy for rare variants (frequency < 1%) by 0.5-3.1% for an array of one million sites and 0.7-7.1% for an array of 500,000 sites, depending on the population. Finally, we show how recent explosive growth in non-African populations means tag SNPs capture on average 30% fewer other variants than in African populations. The unified framework presented here will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.
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http://dx.doi.org/10.1534/g3.118.200502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169386PMC
October 2018

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

Am J Hum Genet 2018 06 31;102(6):1204-1211. Epub 2018 May 31.

Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
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http://dx.doi.org/10.1016/j.ajhg.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992130PMC
June 2018