Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping

Floris Huider; Yuri Milaneschi; René Pool; Bernardo Maciel; Scott Gordon; M Liset Rietman; Almar Kok; Tessel Galesloot; Brittany Mitchell; Leen T Hart; Femke Rutters; Marieke Blom; Didi Rhebergen; Marjolein Visser; Ingeborg Brouwer; Edith Feskens; Catharina Hartman; Albertine Oldehinkel; Mariska Bot; Eco de Geus; Lambertus Kiemeney; Martijn Huisman; H Susan Picavet; Monique Verschuuren; Nicholas Martin; Conor Dolan; Hanna van Loo; Brenda Penninx; Jouke-Jan Hottenga; D Boomsma

doi:10.21203/rs.3.rs-6238738/v1

Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping

Floris Huider
, Yuri Milaneschi
, René Pool
, Bernardo Maciel
, Scott Gordon
, M Liset Rietman
, Almar Kok
, Tessel Galesloot
, Brittany Mitchell
, Leen T Hart
, Femke Rutters
, Marieke Blom
, Didi Rhebergen
, Marjolein Visser
, Ingeborg Brouwer
, Edith Feskens
, Catharina Hartman
, Albertine Oldehinkel
, Mariska Bot
, Eco de Geus

Lambertus Kiemeney, Martijn Huisman, H Susan Picavet, Monique Verschuuren, Nicholas Martin, Conor Dolan, Hanna van Loo, Brenda Penninx, Jouke-Jan Hottenga, D Boomsma

Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)

Research output: Working paper › Preprint › Academic

Abstract

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association study (GWAS) of DSM-defined lifetime Major Depressive Disorder (MDD) in 64,941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. SNP-based heritability was estimated at 13.4%, exceeding recent global meta-analyses, with a high genetic correlation (r = 0.89) to the latest major depression GWAS by the Psychiatric Genetics Consortium (PGC-MD). We identified a novel genome-wide significant locus in PALMD (P = 3.26 × 10⁻⁸), that was confirmed by GWAS-by-subtraction. Polygenic scores (PGSs) based on BIONIC predicted MDD in UKBiobank, and PGSs from PGC-MD predicted into BIONIC, with within-family analyses indicating minimal confounding. Genetic causal inference revealed associations with over 30 phenotypes. Twin concordance for MDD increased with polygenic burden, reinforcing its genetic architecture. This study emphasizes the power of harmonized phenotyping and regional biobanks in uncovering the genetic architecture of MDD, highlighting the value of population-specific studies for improving risk prediction and advancing psychiatric genetics.

Original language	English
Publisher	Research Square Company
Number of pages	35
DOIs	https://doi.org/10.21203/rs.3.rs-6238738/v1
Publication status	Published - 31-Oct-2025

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Name	Research Square
Publisher	Research Square Company
ISSN (Print)	2693-5015

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Huider, F., Milaneschi, Y., Pool, R., Maciel, B., Gordon, S., Rietman, M. L., Kok, A., Galesloot, T., Mitchell, B., Hart, L. T., Rutters, F., Blom, M., Rhebergen, D., Visser, M., Brouwer, I., Feskens, E., Hartman, C., Oldehinkel, A., Bot, M., ... Boomsma, D. (2025). Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping. (Research Square). Research Square Company. https://doi.org/10.21203/rs.3.rs-6238738/v1

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title = "Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping",

abstract = "Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association study (GWAS) of DSM-defined lifetime Major Depressive Disorder (MDD) in 64,941 participants (25.7\% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. SNP-based heritability was estimated at 13.4\%, exceeding recent global meta-analyses, with a high genetic correlation (r = 0.89) to the latest major depression GWAS by the Psychiatric Genetics Consortium (PGC-MD). We identified a novel genome-wide significant locus in PALMD (P = 3.26 × 10⁻⁸), that was confirmed by GWAS-by-subtraction. Polygenic scores (PGSs) based on BIONIC predicted MDD in UKBiobank, and PGSs from PGC-MD predicted into BIONIC, with within-family analyses indicating minimal confounding. Genetic causal inference revealed associations with over 30 phenotypes. Twin concordance for MDD increased with polygenic burden, reinforcing its genetic architecture. This study emphasizes the power of harmonized phenotyping and regional biobanks in uncovering the genetic architecture of MDD, highlighting the value of population-specific studies for improving risk prediction and advancing psychiatric genetics.",

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doi = "10.21203/rs.3.rs-6238738/v1",

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Huider, F, Milaneschi, Y, Pool, R, Maciel, B, Gordon, S, Rietman, ML, Kok, A, Galesloot, T, Mitchell, B, Hart, LT, Rutters, F, Blom, M, Rhebergen, D, Visser, M, Brouwer, I, Feskens, E, Hartman, C , Oldehinkel, A, Bot, M, de Geus, E, Kiemeney, L, Huisman, M, Picavet, HS, Verschuuren, M, Martin, N, Dolan, C, van Loo, H, Penninx, B, Hottenga, J-J & Boomsma, D 2025 'Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping' Research Square, Research Square Company. https://doi.org/10.21203/rs.3.rs-6238738/v1

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T1 - Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping

AU - Huider, Floris

AU - Milaneschi, Yuri

AU - Pool, René

AU - Maciel, Bernardo

AU - Gordon, Scott

AU - Rietman, M Liset

AU - Kok, Almar

AU - Galesloot, Tessel

AU - Mitchell, Brittany

AU - Hart, Leen T

AU - Rutters, Femke

AU - Blom, Marieke

AU - Rhebergen, Didi

AU - Visser, Marjolein

AU - Brouwer, Ingeborg

AU - Feskens, Edith

AU - Hartman, Catharina

AU - Oldehinkel, Albertine

AU - Bot, Mariska

AU - de Geus, Eco

AU - Kiemeney, Lambertus

AU - Huisman, Martijn

AU - Picavet, H Susan

AU - Verschuuren, Monique

AU - Martin, Nicholas

AU - Dolan, Conor

AU - van Loo, Hanna

AU - Penninx, Brenda

AU - Hottenga, Jouke-Jan

AU - Boomsma, D

PY - 2025/10/31

Y1 - 2025/10/31

N2 - Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association study (GWAS) of DSM-defined lifetime Major Depressive Disorder (MDD) in 64,941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. SNP-based heritability was estimated at 13.4%, exceeding recent global meta-analyses, with a high genetic correlation (r = 0.89) to the latest major depression GWAS by the Psychiatric Genetics Consortium (PGC-MD). We identified a novel genome-wide significant locus in PALMD (P = 3.26 × 10⁻⁸), that was confirmed by GWAS-by-subtraction. Polygenic scores (PGSs) based on BIONIC predicted MDD in UKBiobank, and PGSs from PGC-MD predicted into BIONIC, with within-family analyses indicating minimal confounding. Genetic causal inference revealed associations with over 30 phenotypes. Twin concordance for MDD increased with polygenic burden, reinforcing its genetic architecture. This study emphasizes the power of harmonized phenotyping and regional biobanks in uncovering the genetic architecture of MDD, highlighting the value of population-specific studies for improving risk prediction and advancing psychiatric genetics.

AB - Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association study (GWAS) of DSM-defined lifetime Major Depressive Disorder (MDD) in 64,941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. SNP-based heritability was estimated at 13.4%, exceeding recent global meta-analyses, with a high genetic correlation (r = 0.89) to the latest major depression GWAS by the Psychiatric Genetics Consortium (PGC-MD). We identified a novel genome-wide significant locus in PALMD (P = 3.26 × 10⁻⁸), that was confirmed by GWAS-by-subtraction. Polygenic scores (PGSs) based on BIONIC predicted MDD in UKBiobank, and PGSs from PGC-MD predicted into BIONIC, with within-family analyses indicating minimal confounding. Genetic causal inference revealed associations with over 30 phenotypes. Twin concordance for MDD increased with polygenic burden, reinforcing its genetic architecture. This study emphasizes the power of harmonized phenotyping and regional biobanks in uncovering the genetic architecture of MDD, highlighting the value of population-specific studies for improving risk prediction and advancing psychiatric genetics.

U2 - 10.21203/rs.3.rs-6238738/v1

DO - 10.21203/rs.3.rs-6238738/v1

M3 - Preprint

C2 - 41282258

T3 - Research Square

BT - Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping

PB - Research Square Company

ER -

Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping

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