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[Preprint]. 2024 Oct 4:2024.10.02.24314732.

doi: 10.1101/2024.10.02.24314732.

Phenotype harmonization and analysis for The Populations Underrepresented in Mental illness Association Studies (the PUMAS Project)

Ana M Ramirez-Diaz¹, Ana M Diaz-Zuluaga¹, Rocky E Stroud 2nd^{2

3}, Annabel Vreeker^{4

5}, Mary Bitta^{6

7}, Franjo Ivankovic^{8

3}, Olivia Wootton⁹, Cole A Whiteman¹⁰, Hayden Mountcastle^{2

3}, Shaili C Jha^{2

3}, Penelope Georgakopoulos¹¹, Ishpreet Kaur¹, Laura Mena¹, Sandi Asaaf¹, André Luiz de Souza Rodrigues^{12

13

14}, Carolina Ziebold¹⁵, Charles R J C Newton^{7

16

17}, Dan J Stein^{17

18}, Dickens Akena¹⁹, Johanna Valencia-Echeverry²⁰, Joseph Kyebuzibwa¹⁹, Juan D Palacio-Ortiz²⁰, Justin McMahon^{2

3}, Linnet Ongeri²¹, Lori B Chibnik^{3

2}, Lucas C Quarantini²², Lukoye Atwoli^{23

6}, Marcos L Santoro^{24

25}, Mark Baker³, Mateus J A Diniz²⁶, Mauricio Castaño-Ramirez²⁷, Melkam Alemayehu²⁸, Nayana Holanda²⁹, Nohora C Ayola-Serrano³⁰, Pedro G Lorencetti²⁵, Rehema M Mwema⁶, Roxanne James¹⁷, Saulo Albuquerque²⁹, Shivangi Sharma¹¹, Sinéad B Chapman^{3

8

31}, Sintia I Belangero^{25

32}, Solomon Teferra²⁸, Stella Gichuru³³, Susan K Service¹, Symon M Kariuki^{16

7}, Thiago H Freitas^{15

34}, Zukiswa Zingela³⁵, Ary Gadelha¹⁵, Carrie E Bearden^{1

36}, Roel A Ophoff^{1

37}, Benjamin M Neale^{3

8

31}, Alicia R Martin^{8

3

31}, Karestan C Koenen^{3

2

31}, Carlos N Pato¹¹, Carlos Lopez-Jaramillo²⁰, Victor Reus³⁸, Nelson Freimer¹, Michele T Pato¹¹, Bizu Gelaye^{39

2}, Loes Olde Loohuis^{1

37

40}

Affiliations

¹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA.
⁴ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁵ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶ Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
⁷ Department of Psychiatry, University of Oxford, Oxford, UK.
⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital Research Institute, Richard B. Simches Research Building, Boston, USA.
⁹ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹⁰ Robert Wood Johnson Medical School, Rutgers University, New Brunswick, USA.
¹¹ Center for Psychiatric Health and Genomics, Rutgers University, New Brunswick, USA.
¹² Universidade do Estado do Para, Belém, Brazil.
¹³ Hospital de Clinicas Gaspar Vianna, Belém, Brazil.
¹⁴ Centro Universitario do Para, Belém, Brazil.
¹⁵ Federal University of São Paulo - UNIFESP, Department of Psychiatry, São Paulo, Brazil.
¹⁶ Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
¹⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
¹⁸ SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa.
¹⁹ Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
²⁰ Research Group in Psychiatry (GIPSI), Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medellin, Colombia.
²¹ Center for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
²² Universidade Federal da Bahia (UFBA), Salvador, Brazil.
²³ Department of Mental Health and Behavioural Sciences, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya.
²⁴ Disciplina de Biologia Molecular, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil.
²⁵ Laboratory of Integrative Neuroscience (LiNC), Universidade Federal de São Paulo, São Paulo, Brazil.
²⁶ Pax Instituto de Psiquiatria, Goiânia, Brazil.
²⁷ Department of Mental Health and Human Behavior, Universidad de Caldas, Manizales, Colombia.
²⁸ Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
²⁹ Hospital de Saúde Mental Professor Frota Pinto (HSMM), Fortaleza, Brazil.
³⁰ CEMIC Mental Health Clinic, Cartagena, Colombia.
³¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA.
³² Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo,, Brazil.
³³ Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya.
³⁴ University of Fortaleza - UNIFOR, Faculty of Medicine, Fortaleza, Brazil.
³⁵ Executive Dean's Office, Faculty of Health Sciences, Nelson Mandela University, Gqebera, South Africa.
³⁶ Department of Psychology, University of California Los Angeles, Los Angeles, USA.
³⁷ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.
³⁸ Department of Psychiatry and Behavioral Sciences, UCSF School of Medicine, UCSF Weill Institute for Neurosciences, San Francisco, USA.
³⁹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, USA.
⁴⁰ Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.

PMID: 39502669
PMCID: PMC11537327
DOI: 10.1101/2024.10.02.24314732

Phenotype harmonization and analysis for The Populations Underrepresented in Mental illness Association Studies (the PUMAS Project)

Ana M Ramirez-Diaz et al. medRxiv. 2024.

[Preprint]. 2024 Oct 4:2024.10.02.24314732.

doi: 10.1101/2024.10.02.24314732.

Authors

Affiliations

¹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA.
⁴ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁵ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶ Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
⁷ Department of Psychiatry, University of Oxford, Oxford, UK.
⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital Research Institute, Richard B. Simches Research Building, Boston, USA.
⁹ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹⁰ Robert Wood Johnson Medical School, Rutgers University, New Brunswick, USA.
¹¹ Center for Psychiatric Health and Genomics, Rutgers University, New Brunswick, USA.
¹² Universidade do Estado do Para, Belém, Brazil.
¹³ Hospital de Clinicas Gaspar Vianna, Belém, Brazil.
¹⁴ Centro Universitario do Para, Belém, Brazil.
¹⁵ Federal University of São Paulo - UNIFESP, Department of Psychiatry, São Paulo, Brazil.
¹⁶ Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
¹⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
¹⁸ SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa.
¹⁹ Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
²⁰ Research Group in Psychiatry (GIPSI), Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medellin, Colombia.
²¹ Center for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
²² Universidade Federal da Bahia (UFBA), Salvador, Brazil.
²³ Department of Mental Health and Behavioural Sciences, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya.
²⁴ Disciplina de Biologia Molecular, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil.
²⁵ Laboratory of Integrative Neuroscience (LiNC), Universidade Federal de São Paulo, São Paulo, Brazil.
²⁶ Pax Instituto de Psiquiatria, Goiânia, Brazil.
²⁷ Department of Mental Health and Human Behavior, Universidad de Caldas, Manizales, Colombia.
²⁸ Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
²⁹ Hospital de Saúde Mental Professor Frota Pinto (HSMM), Fortaleza, Brazil.
³⁰ CEMIC Mental Health Clinic, Cartagena, Colombia.
³¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA.
³² Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo,, Brazil.
³³ Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya.
³⁴ University of Fortaleza - UNIFOR, Faculty of Medicine, Fortaleza, Brazil.
³⁵ Executive Dean's Office, Faculty of Health Sciences, Nelson Mandela University, Gqebera, South Africa.
³⁶ Department of Psychology, University of California Los Angeles, Los Angeles, USA.
³⁷ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.
³⁸ Department of Psychiatry and Behavioral Sciences, UCSF School of Medicine, UCSF Weill Institute for Neurosciences, San Francisco, USA.
³⁹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, USA.
⁴⁰ Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.

PMID: 39502669
PMCID: PMC11537327
DOI: 10.1101/2024.10.02.24314732

Abstract

Background: The Populations Underrepresented in Mental illness Association Studies (PUMAS) project is attempting to remediate the historical underrepresentation of African and Latin American populations in psychiatric genetics through large-scale genetic association studies of individuals diagnosed with a serious mental illness [SMI, including schizophrenia (SCZ), schizoaffective disorder (SZA) bipolar disorder (BP), and severe major depressive disorder (MDD)] and matched controls. Given growing evidence indicating substantial symptomatic and genetic overlap between these diagnoses, we sought to enable transdiagnostic genetic analyses of PUMAS data by conducting phenotype alignment and harmonization for 89,320 participants (48,165 cases and 41,155 controls) from four cohorts, each of which used different ascertainment and assessment methods: PAISA n=9,105; PUMAS-LATAM n=14,638; NGAP n=42,953 and GPC n=22,624. As we describe here, these efforts have yielded harmonized datasets enabling us to analyze PUMAS genetic variation data at three levels: SMI overall, diagnoses, and individual symptoms.

Methods: In aligning item-level phenotypes obtained from 14 different clinical instruments, we incorporated content, branching nature, and time frame for each phenotype; standardized diagnoses; and selected 19 core SMI item-level phenotypes for analyses. The harmonization was evaluated in PUMAS cases using multiple correspondence analysis (MCA), co-occurrence analyses, and item-level endorsement.

Outcomes: We mapped >6,895 item-level phenotypes in the aggregated PUMAS data, in which SCZ (44.97%) and severe BP (BP-I, 31.53%) were the most common diagnoses. Twelve of the 19 core item-level phenotypes occurred at frequencies of > 10% across all diagnoses, indicating their potential utility for transdiagnostic genetic analyses. MCA of the 14 phenotypes that were present for all cohorts revealed consistency across cohorts, and placed MDD and SCZ into separate clusters, while other diagnoses showed no significant phenotypic clustering.

Interpretation: Our alignment strategy effectively aggregated extensive phenotypic data obtained using diverse assessment tools. The MCA yielded dimensional scores which we will use for genetic analyses along with the item level phenotypes. After successful harmonization, residual phenotypic heterogeneity between cohorts reflects differences in branching structure of diagnostic instruments, recruitment strategies, and symptom interpretation (due to cultural variation).

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Figures

**Figure 1.. Recruitment countries (A) and sample sizes (B) of PUMAS cohorts**
including NGAP, GPC, PAISA, and PUMAS-LATAM. For cohorts with ongoing inclusion (GPC) data freezes up to August 2024 were used (see also Table 1).

**Figure 2.. PUMAS-wide Multiple Correspondence Analysis (MCA)**
(**A & B**) depict the first two dimensions (Dim1 and Dim2) of an MCA performed using item-level phenotypes assessed in all cohorts (positive psychotic symptoms, delusions, hallucinations, negative psychotic symptoms, irritability, flight ideas, grandiosity, lifetime manic episode, lifetime depressive episode, suicidality, anhedonia, sleep disturbances, decreased need of sleep, and fatigue). Individuals are colored by cohort (NGAP, GPC, PAISA, PUMAS-LATAM (A) and by Diagnosis (BP-I, Other BP, SZA, SCZ, and MDD) (B). The percentage of variation (inertia) explained by each dimension is indicated in parentheses. The marginal box plots summarize the distribution of the MCA scores along Dim1 and Dim2 for each cohort or diagnosis group. The central line in each box represents the median of the data, while the hinges of the box indicate the first and third quartiles. (C) Visualizes the variable correlations to the MCA dimensions.

**Figure 3.. Jaccard similarity matrix of phenotypes including all PUMAS cohorts.**
Each cell in the matrix corresponds to the Jaccard’s Similarity of two phenotypes, calculated as the proportion of instances where both phenotypes are endorsed relative to the total number of instances where at least one of the phenotypes is endorsed. The gradient scale from light to dark reflects the range of Jaccard Similarity Scores, from 0 (no similarity) to 1 (perfect similarity).

**Figure 4.. Phenotype endorsement by cohort and diagnosis**
Colored dots represent phenotypic data availability per cohort.

See this image and copyright information in PMC

References

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1. Singh T. et al. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature 604, 509–516 (2022). - PMC - PubMed
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This is a preprint.

Phenotype harmonization and analysis for The Populations Underrepresented in Mental illness Association Studies (the PUMAS Project)

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Phenotype harmonization and analysis for The Populations Underrepresented in Mental illness Association Studies (the PUMAS Project)

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Abstract

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References

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