Neurogenetics and Multi-omics of Neuroinflammatory Diseases in Multiplex Families to Improve Patients Health (NeuroDIP)
The goal of this observational study is to learn why some families have several members with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), or MOG antibody-associated disease (MOGAD). These diseases happen when the immune system attacks the brain, optic nerves, or spinal cord. The study includes about 500 people from about 100 families: people with one of these diseases and their relatives who do not have it. The main question is: Do rare gene changes (variants) shared by family members explain why these diseases run in families? Researchers will compare the DNA of family members who have the disease with the DNA of relatives who do not. They will also look at how genes are switched on and off in blood cells. Participants will:
- Attend one visit of 2 to 3 hours at one of five French hospitals
- Answer questions about their health, treatments, and family history
- Give a 50 mL blood sample
研究概览
地位
详细说明
Background: Large genetic studies have found many common gene variants that raise the risk of multiple sclerosis, but they explain only part of the inherited risk. They also explain familial forms poorly. Rare variants with a strong effect may be shared within a family and go unnoticed in studies of unrelated people. Families with several affected members are well suited to finding them. NeuroDIP combines genetic, epigenetic (DNA methylation), and gene expression data from these families and links them to clinical information.
Design: This is a cross-sectional, family-based study with a single visit and no follow-up. Comparing affected members with unaffected relatives from the same family helps limit the effect of ancestry and of factors that relatives share.
Visit: At the hospital, participants give written consent and have a short physical examination. Patients also have a disability assessment (EDSS). The investigator draws a family tree and records medical history, treatments, lifestyle, and any previous brain MRI report. A blood sample is then drawn. The study does not change usual medical care. Relatives are invited through the affected family member and are contacted by the investigating centre.
Samples and data: Samples and data carry a code, and names are kept only at the investigating centre. Samples are processed and stored in accredited biological resource centres. Research data are stored on secure servers in France and are not transferred outside the European Union. With participants' consent, coded data and samples may be used in future research on neuroinflammatory diseases, including deposit in the French MS registry (OFSEP).
Results: Participants do not receive individual research results. The exception is an incidental finding with health consequences, and participants must agree to be informed of such a finding before they take part. Participants can ask for the overall results and may be invited to an optional information meeting for families.
Funding: The study is funded by the Inserm Messidore 2024 call and by the ARSEP Foundation, and belongs to the NeuroDINet network on neuroinflammatory diseases.
研究类型
注册 (估计的)
阶段
- 不适用
联系人和位置
学习联系方式
- 姓名：David Axel LAPLAUD, MD PhD
- 电话号码：+33 240165176
- 邮箱：david.laplaud@chu-nantes.fr
研究联系人备份
- 姓名：Nicolas VINCE, PhD
- 电话号码：+33 253526229
- 邮箱：nicolas.vince@univ-nantes.fr
学习地点
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Bron、法国、69500
- Hospice Civil de Lyon - Hospital Pierre Wertheimer
-
接触：
- Sandra VUKUSIC
- 电话号码：+33 04 72 68 13 13
- 邮箱：sandra.vukusic@chu-lyon.fr
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首席研究员：
- Sandra Vukusic
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Nantes、法国、44000
- University Hospital Laennec
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首席研究员：
- David-Axel LAPLAUD
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接触：
- David-Axel LAPLAUD
- 电话号码：+33 02 40 16 52 00
- 邮箱：david.laplaud@chu-nantes.fr
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Nice、法国、06002
- University Hospital Pasteur 2
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首席研究员：
- Christine LEBRUN-FRENAY
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接触：
- Christine LEBRUN-FRENAY
- 电话号码：+33 04 92 03 71 00
- 邮箱：lebrun-frenay.c@chu-nice.fr
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Paris、法国、75013
- Assistance Publique Hôpitaux de Paris- La Pitié Salpêtrière Hospital
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接触：
- Céline a LOUAPRE
- 电话号码：+33 01 42 16 57 66
- 邮箱：celine.louapre@aphp.fr
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首席研究员：
- Céline LOUAPRE
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Rennes、法国、35000
- University Hospital Pontchaillou
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首席研究员：
- Laure MICHEL
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接触：
- Laure MICHEL
- 电话号码：+33 02 99 28 42 66
- 邮箱：laure.michel@chu-rennes.fr
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
-
Affected participants:
- Age 15 years and 3 months or older
- Multiple sclerosis (2024 McDonald criteria), neuromyelitis optica spectrum disorder with anti-AQP4 antibodies (2015 Wingerchuk criteria), or MOG antibody-associated disease (2023 international MOGAD panel criteria)
- Member of a multiplex family: at least two affected members sharing at least 12.5% of their genetic heritage
- Affiliated to a social security scheme or equivalent
- Written informed consent (for minors: assent of the minor and consent of the holders of parental authority)
-
Unaffected relatives:
- Age 18 years or older
- Sharing at least 25% of genetic heritage with one of the two affected family members
- No multiple sclerosis, NMOSD, MOGAD, or other known inflammatory disease of the central nervous system
- Affiliated to a social security scheme or equivalent
- Written informed consent
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Transcriptomic sub-cohort (30 to 60 participants, about 10 families):
- Patients with no immunomodulatory or immunosuppressive treatment for at least 12 months, and their relatives
Exclusion Criteria:
- Refusal to participate before the inclusion visit
- Inability to understand the study information or to consent
- Person under guardianship, curatorship or legal protection
- Person deprived of liberty by judicial or administrative decision
- Pregnant or breastfeeding woman
- No kinship with at least one affected member of the included family
- Refusal to be informed of an incidental discovery of a pathogenic genetic variant
学习计划
研究是如何设计的？
设计细节
- 主要用途：基础科学
- 分配：不适用
- 介入模型：单组作业
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
|
其他：Multiplex family members (patients and relatives)
Four participant categories (people with MS, NMOSD, MOGAD, and healthy) with their approximate numbers. |
One venous blood sample (50 mL) is drawn at a single visit. DNA is used for whole-genome sequencing. Cryopreserved peripheral blood mononuclear cells (PBMCs) are used for DNA methylation profiling and RNA sequencing. Serum is used to measure GFAP and NfL. |
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Rare high-penetrance variants co-segregating with disease within multiplex families.
大体时间：36 months from the first inclusion.
|
Proportion of rare (minor allele frequency < 1%), high-penetrance variants found in affected members and absent or significantly less frequent in unaffected relatives of the same family sharing at least 25% of their genetic heritage. Assessed by co-segregation and linkage analysis, family-based association tests and in silico prediction of variant impact. |
36 months from the first inclusion.
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
eQTL: genetic loci associated with gene expression in PBMC
大体时间：36 months from the first inclusion.
|
Loci where genetic variants are associated with differences in gene expression in peripheral blood mononuclear cells (PBMC), from integrated whole genome sequencing and RNA sequencing data, in the untreated patient sub-group and their relatives. |
36 months from the first inclusion.
|
|
Disease-associated DNA methylation (CpG sites)
大体时间：36 months from the first inclusion.
|
Number and type of CpG sites differentially methylated between patients and unaffected relatives, measured with EPIC arrays on PBMC DNA, in the untreated patient sub-group and their relatives. |
36 months from the first inclusion.
|
|
Transcriptomic signatures of PBMC subpopulations
大体时间：36 months from the first inclusion.
|
Differentially expressed genes and perturbed pathways in immune cell subpopulations, from bulk and single-cell RNA sequencing of PBMC, comparing untreated patients (dedicated sub-cohort, n = 30 to 60) with their unaffected relatives. |
36 months from the first inclusion.
|
|
Multi-omic molecular signatures
大体时间：36 months from the first inclusion.
|
Molecular signatures obtained by integrating genomic, DNA methylation and transcriptomic data (omicsNPC framework, multilevel modelling), used to model familial risk. |
36 months from the first inclusion.
|
|
Evaluation of the correlation with the disease phenotype
大体时间：36 months from the first inclusion.
|
A potential correlation will be evaluated between genetic variants, DNA methylation, gene expression profiles and clinical data (age at onset , disease course, treatment response ) of patient. |
36 months from the first inclusion.
|
合作者和调查者
调查人员
- 首席研究员：Nicolas VINCE, PhD、Nantes Université
出版物和有用的链接
一般刊物
- International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019 Sep 27;365(6460):eaav7188. doi: 10.1126/science.aav7188.
- Horjus J, van Mourik-Banda T, Heerings MAP, Hakobjan M, De Witte W, Heersema DJ, Jansen AJ, Strijbis EMM, de Jong BA, Slettenaar AEJ, Zeinstra EMPE, Hoogervorst ELJ, Franke B, Kruijer W, Jongen PJ, Visser LJ, Poelmans G. Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis. Int J Mol Sci. 2022 Sep 28;23(19):11461. doi: 10.3390/ijms231911461.
- Wannaphut C, Ongphichetmetha T, Satiraphan P, Jitprapaikulsan J, Apiwattanakul M, Siritho S, Prayoonwiwat N, Savangned P, Rattanathamsakul N. Familial neuromyelitis optica spectrum disorders: Case series and systematic review. Mult Scler Relat Disord. 2023 May;73:104627. doi: 10.1016/j.msard.2023.104627. Epub 2023 Mar 21.
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他相关的 MeSH 术语
其他研究编号
- C25-79
- 2026-A01125-46 (注册表标识符：IDRCB)
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