Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy
Background Neurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes...
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creator | Vacher, Michael Porter, Tenielle Milicic, Lidija Dore, Vincent Bourgeat, Pierrick Villemagne, Victor L.L. Doecke, James D. Laws, Simon M. Heng, Julian Ik‐Tsen |
description | Background
Neurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes that occur in Alzheimer’s disease, is poorly characterised. Here, we investigated the associations between Single Nucleotide Polymorphisms (SNPs) in neurodevelopmental genes and brain volumetrics.
Method
From a curated list of 40 genes related to neurodevelopmental processes, we identified a set of 233 independent SNPs. The genotype data was generated from 715 unrelated individuals (Amyloid Beta (Ab) ‐ N=328, Ab+ N=387), enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on the cortical grey, subcortical white matter, ventricular, and hippocampal volumes and used linear mixed models to assess whether specific genotypes were associated to regional volume changes over time. The associations with the traits of interest were assessed cross‐sectionally at baseline and longitudinally, over a 12‐year time span.
Result
At baseline, cross‐sectional analyses revealed one significant association between the variant, rs2923137, located in DRC7 ( |
doi_str_mv | 10.1002/alz.051974 |
format | Article |
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Neurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes that occur in Alzheimer’s disease, is poorly characterised. Here, we investigated the associations between Single Nucleotide Polymorphisms (SNPs) in neurodevelopmental genes and brain volumetrics.
Method
From a curated list of 40 genes related to neurodevelopmental processes, we identified a set of 233 independent SNPs. The genotype data was generated from 715 unrelated individuals (Amyloid Beta (Ab) ‐ N=328, Ab+ N=387), enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on the cortical grey, subcortical white matter, ventricular, and hippocampal volumes and used linear mixed models to assess whether specific genotypes were associated to regional volume changes over time. The associations with the traits of interest were assessed cross‐sectionally at baseline and longitudinally, over a 12‐year time span.
Result
At baseline, cross‐sectional analyses revealed one significant association between the variant, rs2923137, located in DRC7 (<20KB KATNB1) and ventricular volume (p = 2.13e‐4, β = 5.8). In the longitudinal analyses, we found that rs1142749, a marker located near TUBB4B, was consistently associated with accelerated rate of change in grey matter (p = 9.2e‐4, β = 0.034), hippocampal (p = 2.9e‐3, β = 0.025) and ventricular volume (p = 2.1e‐3, β = ‐0.028). Further, we observed that the strength and effects of these associations were exacerbated in Ab+ individuals but were absent in Ab negative sub‐population. Another noticeable link was identified between rs2555172 (DCHS1) and hippocampal volume change (p = 1.4e‐3, β = ‐0.024). The identified associations were independent of variation due to the APOE e4 allele and remained significant after correction for multiple comparisons.
Conclusion
The results support the hypothesis that genes associated with neurodevelopmental processes and signalling mechanisms are relevant to Alzheimer’s Disease. The identified associations suggest that mutations in key neurodevelopment genes could be linked to accelerated atrophy in specific areas of the brain.</description><identifier>ISSN: 1552-5260</identifier><identifier>EISSN: 1552-5279</identifier><identifier>DOI: 10.1002/alz.051974</identifier><language>eng</language><ispartof>Alzheimer's & dementia, 2021-12, Vol.17 (S5), p.n/a</ispartof><rights>2021 the Alzheimer's Association</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falz.051974$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falz.051974$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids></links><search><creatorcontrib>Vacher, Michael</creatorcontrib><creatorcontrib>Porter, Tenielle</creatorcontrib><creatorcontrib>Milicic, Lidija</creatorcontrib><creatorcontrib>Dore, Vincent</creatorcontrib><creatorcontrib>Bourgeat, Pierrick</creatorcontrib><creatorcontrib>Villemagne, Victor L.L.</creatorcontrib><creatorcontrib>Doecke, James D.</creatorcontrib><creatorcontrib>Laws, Simon M.</creatorcontrib><creatorcontrib>Heng, Julian Ik‐Tsen</creatorcontrib><title>Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy</title><title>Alzheimer's & dementia</title><description>Background
Neurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes that occur in Alzheimer’s disease, is poorly characterised. Here, we investigated the associations between Single Nucleotide Polymorphisms (SNPs) in neurodevelopmental genes and brain volumetrics.
Method
From a curated list of 40 genes related to neurodevelopmental processes, we identified a set of 233 independent SNPs. The genotype data was generated from 715 unrelated individuals (Amyloid Beta (Ab) ‐ N=328, Ab+ N=387), enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on the cortical grey, subcortical white matter, ventricular, and hippocampal volumes and used linear mixed models to assess whether specific genotypes were associated to regional volume changes over time. The associations with the traits of interest were assessed cross‐sectionally at baseline and longitudinally, over a 12‐year time span.
Result
At baseline, cross‐sectional analyses revealed one significant association between the variant, rs2923137, located in DRC7 (<20KB KATNB1) and ventricular volume (p = 2.13e‐4, β = 5.8). In the longitudinal analyses, we found that rs1142749, a marker located near TUBB4B, was consistently associated with accelerated rate of change in grey matter (p = 9.2e‐4, β = 0.034), hippocampal (p = 2.9e‐3, β = 0.025) and ventricular volume (p = 2.1e‐3, β = ‐0.028). Further, we observed that the strength and effects of these associations were exacerbated in Ab+ individuals but were absent in Ab negative sub‐population. Another noticeable link was identified between rs2555172 (DCHS1) and hippocampal volume change (p = 1.4e‐3, β = ‐0.024). The identified associations were independent of variation due to the APOE e4 allele and remained significant after correction for multiple comparisons.
Conclusion
The results support the hypothesis that genes associated with neurodevelopmental processes and signalling mechanisms are relevant to Alzheimer’s Disease. The identified associations suggest that mutations in key neurodevelopment genes could be linked to accelerated atrophy in specific areas of the brain.</description><issn>1552-5260</issn><issn>1552-5279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kMtOwzAQRS0EEqWw4Qu8RmqxUzuOl1XFo1IlNqzYRJNknBo5duSEorKBT-Ab-RLSh1iymtG5Z2ZxCbnmbMoZS27BfUyZ5FqJEzLiUiYTmSh9-ren7JxcdN0rY4JlXI7I57JC31tjS-ht8DQY6vEthgo36ELbDCE4WqNHuoFowfcdtU3rdj5W1HoKNf58fUd0e1BEGFgTYrsOLtSD5mi5Bl9jR8FXtAyx30PoY2jX20tyZsB1eHWcY_J8f_e8eJysnh6Wi_lqUiolJlIwprNEg051WRRZliJLCia1kBKkEohCGWMqUc44Gl0ZlWaJqjDNUkAsitmY3BzeljF0XUSTt9E2ELc5Z_muuXxoLj80N8j8IL9bh9t_zHy-ejne_AJdxXWK</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Vacher, Michael</creator><creator>Porter, Tenielle</creator><creator>Milicic, Lidija</creator><creator>Dore, Vincent</creator><creator>Bourgeat, Pierrick</creator><creator>Villemagne, Victor L.L.</creator><creator>Doecke, James D.</creator><creator>Laws, Simon M.</creator><creator>Heng, Julian Ik‐Tsen</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>202112</creationdate><title>Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy</title><author>Vacher, Michael ; Porter, Tenielle ; Milicic, Lidija ; Dore, Vincent ; Bourgeat, Pierrick ; Villemagne, Victor L.L. ; Doecke, James D. ; Laws, Simon M. ; Heng, Julian Ik‐Tsen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c774-54009829a969cbb886e02b059455a574ee47fffd4c31ef9df76827de686aeebb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vacher, Michael</creatorcontrib><creatorcontrib>Porter, Tenielle</creatorcontrib><creatorcontrib>Milicic, Lidija</creatorcontrib><creatorcontrib>Dore, Vincent</creatorcontrib><creatorcontrib>Bourgeat, Pierrick</creatorcontrib><creatorcontrib>Villemagne, Victor L.L.</creatorcontrib><creatorcontrib>Doecke, James D.</creatorcontrib><creatorcontrib>Laws, Simon M.</creatorcontrib><creatorcontrib>Heng, Julian Ik‐Tsen</creatorcontrib><collection>CrossRef</collection><jtitle>Alzheimer's & dementia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vacher, Michael</au><au>Porter, Tenielle</au><au>Milicic, Lidija</au><au>Dore, Vincent</au><au>Bourgeat, Pierrick</au><au>Villemagne, Victor L.L.</au><au>Doecke, James D.</au><au>Laws, Simon M.</au><au>Heng, Julian Ik‐Tsen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy</atitle><jtitle>Alzheimer's & dementia</jtitle><date>2021-12</date><risdate>2021</risdate><volume>17</volume><issue>S5</issue><epage>n/a</epage><issn>1552-5260</issn><eissn>1552-5279</eissn><abstract>Background
Neurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes that occur in Alzheimer’s disease, is poorly characterised. Here, we investigated the associations between Single Nucleotide Polymorphisms (SNPs) in neurodevelopmental genes and brain volumetrics.
Method
From a curated list of 40 genes related to neurodevelopmental processes, we identified a set of 233 independent SNPs. The genotype data was generated from 715 unrelated individuals (Amyloid Beta (Ab) ‐ N=328, Ab+ N=387), enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on the cortical grey, subcortical white matter, ventricular, and hippocampal volumes and used linear mixed models to assess whether specific genotypes were associated to regional volume changes over time. The associations with the traits of interest were assessed cross‐sectionally at baseline and longitudinally, over a 12‐year time span.
Result
At baseline, cross‐sectional analyses revealed one significant association between the variant, rs2923137, located in DRC7 (<20KB KATNB1) and ventricular volume (p = 2.13e‐4, β = 5.8). In the longitudinal analyses, we found that rs1142749, a marker located near TUBB4B, was consistently associated with accelerated rate of change in grey matter (p = 9.2e‐4, β = 0.034), hippocampal (p = 2.9e‐3, β = 0.025) and ventricular volume (p = 2.1e‐3, β = ‐0.028). Further, we observed that the strength and effects of these associations were exacerbated in Ab+ individuals but were absent in Ab negative sub‐population. Another noticeable link was identified between rs2555172 (DCHS1) and hippocampal volume change (p = 1.4e‐3, β = ‐0.024). The identified associations were independent of variation due to the APOE e4 allele and remained significant after correction for multiple comparisons.
Conclusion
The results support the hypothesis that genes associated with neurodevelopmental processes and signalling mechanisms are relevant to Alzheimer’s Disease. The identified associations suggest that mutations in key neurodevelopment genes could be linked to accelerated atrophy in specific areas of the brain.</abstract><doi>10.1002/alz.051974</doi><tpages>1</tpages></addata></record> |
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title | Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy |
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