A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder

Zeng, Yanni; Navarro, Pau; Fernandez-Pujals, Ana Maria; Hall, Lynsey S.; Clarke, Toni‐Kim; Thomson, Pippa A.; Smith, Blair H.; Hocking, Lynne J.; Padmanabhan, Sandosh; Hayward, Caroline; MacIntyre, Donald J.; Wray, Naomi R.; Deary, Ian J.; Porteous, David J.; Haley, Chris; McIntosh, Andrew M.

doi:10.1016/j.biopsych.2016.04.017

Cited by 32 publications

(46 citation statements)

References 41 publications

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“…Among the replicated genome‐wide associations, NEGR1 (neuronal growth regulator 1) shows a role in synaptic plasticity in MDD‐relevant brain regions such as the cortex, hypothalamus, and hippocampus (Hashimoto, Maekawa, & Miyata, ; Sanz, Ferraro, & Fournier, ; Schäfer, Bräuer, Savaskan, Rathjen, & Brümmendorf, ) . DCC (Netrin 1 receptor) also looks promising as it is one of the most relevant genes contributing to the association between the NETRIN signaling pathway and MDD in different samples (Zeng et al, ).…”

Section: Genome‐wide Association Studiesmentioning

confidence: 99%

Genetics of resilience: Implications from genome‐wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression

Maul

Giegling

Fabbri

et al. 2019

American J of Med Genetics Pt B

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Resilience is the ability to cope with critical situations through the use of personal and socially mediated resources. Since a lack of resilience increases the risk of developing stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), a better understanding of the biological background is of great value to provide better prevention and treatment options. Resilience is undeniably influenced by genetic factors, but very little is known about the exact underlying mechanisms. A recently published genome-wide association study (GWAS) on resilience has identified three new susceptibility loci, DCLK2, KLHL36, and SLC15A5. Further interesting results can be found in association analyses of gene variants of the stress response system, which is closely related to resilience, and PTSD and MDD. Several promising genes, such as the COMT (catechol-O-methyltransferase) gene, the serotonin transporter gene (SLC6A4), and neuropeptide Y (NPY) suggest gene × environment interaction between genetic variants, childhood adversity, and the occurrence of PTSD and MDD, indicating an impact of these genes on resilience. GWAS on PTSD and MDD provide another approach to identifying new disease-associated loci and, although the functional significance for disease development for most of these risk genes is still unknown, they are potential candidates due to the overlap of stress-related psychiatric disorders and resilience. In the future, it will be important for genetic studies to focus more on resilience than on pathological phenotypes, to develop reasonable concepts for measuring resilience, and to establish international cooperations to generate sufficiently large samples. K E Y W O R D S depression, genetic risk factors, posttraumatic stress disorder, resilience, vulnerability

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Section: Genome‐wide Association Studiesmentioning

confidence: 99%

Genetics of resilience: Implications from genome‐wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression

Maul

Giegling

Fabbri

et al. 2019

American J of Med Genetics Pt B

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“…Genic SNPs found in the NETRIN1 signaling pathway as taken from Zeng et al's (2017) study (14) (N genes = 43; gene list is presented in the Supplementary Material, table S3) and genic SNPs excluded from the pathway were annotated using the program ANNOVAR.…”

Section: Snp Annotationmentioning

confidence: 99%

“…Following several GWAS, the Psychiatric Genomics Consortium (PGC) have identified an aggregation of variants in several specific biological pathways (12; 13). In MDD, Zeng et al (2017) (14) combined pathway analysis and regional heritability analysis in two independent samples and reported that the NETRIN1 signaling pathway was involved in the genetic aetiology of MDD. Moreover, polygenic risk scores (PRS) calculated for this pathway alone more accurately predicted MDD in one of the cohorts compared to PRS calculated for the whole genome.…”

Section: Introductionmentioning

confidence: 99%

Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and thalamic radiation white matter microstructure in UK Biobank

Barbu

Zeng

Shen

et al. 2018

Preprint

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Background: Major Depressive Disorder (MDD) is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome, and growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide an important route for identification of disease mechanisms by focusing on a specific process excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether MDD polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and the whole genome excluding NETRIN1 pathway genes (genomic-PRS) were associated with white matter integrity. Methods:We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: N = 6,401; MD: N = 6,390). Results:We found significantly lower FA in the superior longitudinal fasciculus (β = -0.035, pcorrected = 0.029) and significantly higher MD in a global measure of thalamic radiations (β = 0.029, pcorrected = 0.021), as well as higher MD in the superior (β = 0.034, pcorrected = 0.039) and inferior (β = 0.029, pcorrected = 0.043) longitudinal fasciculus and in the anterior (β = 0.025, pcorrected = 0.046) and superior (β = 0.027, pcorrected = 0.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. Conclusions:Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for MDD through effects on thalamic radiation white matter microstructure.

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“…In the present study, we tested whether DCC-haploinsufficient humans exhibit mesocorticolimbic connectivity alterations and associated behavioral traits similar to those identified in Dcc-heterozygous mice. The sample comprised a large four-generational Quebec family, half of whom are carriers for an autosomal dominant mutation that induces DCC haploinsufficiency (Srour et al, 2009(Srour et al, , 2010. Within the family, a genome-wide linkage analysis identified a DCC frameshift mutation (NM_005215.3, c.1140 ϩ 1GϾA) resulting from abnormal skipping of exon 6.…”

Section: Introductionmentioning

confidence: 99%

Mesocorticolimbic Connectivity and Volumetric Alterations inDCCMutation Carriers

Vosberg

Zhang²,

Menegaux

et al. 2018

J. Neurosci.

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The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in -haploinsufficient mice. The human volunteers were 20 mutation carriers, 16 relatives, and 20 unrelated healthy volunteers (UHVs; 28 females). The mice were 11 and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [: = 0.0005,() = 0.60; UHV: = 0.0029, = 0.48] and ventral medial prefrontal cortex (: = 0.0031, = 0.53; UHV: = 0.034, = 0.35); (2) lower novelty-seeking scores (: = 0.034, = 0.82; UHV: = 0.019, = 0.84); and (3) reduced striatal volume (: = 0.0009, = 1.37; UHV: = 0.0054, = 0.93). Striatal volumetric reductions were also present in mice, and these were seen during adolescence ( = 0.0058, = 1.09) and adulthood ( = 0.003, = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which mutations might affect susceptibility to diverse neuropsychiatric disorders. Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, , enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

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A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder

Cited by 32 publications

References 41 publications

Genetics of resilience: Implications from genome‐wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression

Genetics of resilience: Implications from genome‐wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression

Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and thalamic radiation white matter microstructure in UK Biobank

Mesocorticolimbic Connectivity and Volumetric Alterations inDCCMutation Carriers

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