Background: Genome-wide association studies conducted for brain imaging measures have identified common genetic variants with modest effect sizes that reside mainly in non-coding regions. We sought to identify rare variants influencing these measures in the Framingham Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. Methods: We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age and total intracranial volume with individual variants while accounting for familial relatedness. Gene-based tests were conducted for rare variants using 1) a sliding-window approach, 2) a selection of functional exonic variants or 3) all variants. Results: We detected new loci in 1p21 for cerebral volume (minor allele frequency (MAF) =0.005, P=10-8) and in 16q23 for hippocampal volume (MAF=0.05, P=2.7x10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, P=4.4x10-4) and in 17q25 for WMH (rs7214628, P=2.0x10-3) were confirmed. Gene-based tests detected associations (P≤2.3x10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including several Alzheimer (UNC5D) and Parkinson’s disease (GBA) associated genes. Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, Alzheimer and Parkinson’s disease pathways. Conclusions: Whole genome sequence wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is ongoing to confirm these findings. Supported by: R01 AG033193, R01 AG008122, R01 AG049505, R01 AG049607, R01 NS017950, R01 AG054076, FHS contract HHSN268201500001I

Objective: Genome-Wide Association Studies have identified common genetic variants with modest effect sizes, and most associated variants reside in non-coding regions. We sought to identify rare variants influencing brain MRI measures in the Framingham Study (FHS) by performing Whole Genome Sequence (WGS) analyses within the Trans-Omics for Precision Medicine (TOPMed) Program.
Background: Brain MRI measures such as Total Cerebral Brain Volume (TCBV), Hippocampal Volume (HPV) and White Matter Hyperintensities (WMH) are endophenotypes of Alzheimer disease (AD) and vascular injury. Identifying loci influencing these measures may reveal new genes and biological mechanisms underlying these diseases.
Design/Methods: A total of 2,180, 2,170 and 1,667 individuals were included in the WGS analyses of TCBV, HPV and WMH respectively. Rank-normalized residuals from mixed effect linear regression models adjusted for sex, age and total intracranial volume were tested for association with individual variants while accounting for familial relatedness. Gene-based tests were conducted for rare variants (Minor Allele Frequency (MAF) lower or equal to 1%) with SKAT or burden test within genes using 1) a sliding-window approach, 2) a selection of functional exonic variants or 3) all variants.
Results: WGS analyses revealed new loci at the genome-wide level (P lower or equal to 5x10-8) in 1p21 for TCBV between RWDD3 and PTBP2 (MAF=0.005, P=10-8) and in 16q23 for HPV within LOC102724084 (MAF ~5%, P=2.7x10-8). The known associations in 12q24 for HPV (P lower or equal to 0.01) and in 17q25 for WMH (P lower or equal to 6.7x10-6) were observed. Gene-based tests applied to genes and performed using a sliding-window approach detected genome-wide associations (P lower or equal to 2.3x10-6) in new loci with SKAT for TCBV (FCHO2 in 5q13, UNC5D in 8p12, CCDC33 in 15q24) and HPV (LRRTM4 in 2p12) and with the burden test for TCBV (C9orf84 in 9q31, UBL3 in 13q12-q13, SYT3 in 19q13) and WMH (ALCAM in 3q13, GBA3 in 4p15). SKAT method applied to all variants within genes detected SOCS7 in 17q12 significantly associated with TCBV.
Conclusion: In conclusion, WGS-wide search for brain MRI measures reveals intriguing new loci influencing brain volumes.
Study supported by: R01 AG033193, R01 AG008122, R01 AG049505, R01 AG049607, R01 NS017950, R01 AG054076, FHS contract HHSN268201500001I
Disclosures: No disclosure

Background: Brain MRI measures such as Total Brain Volume (TBV), Hippocampal Volume (HPV) and White Matter Hyperintensities (WMH) are endophenotypes of Alzheimer disease (AD) and vascular injury. Identifying loci influencing these measures may reveal new genes and biological mechanisms underlying these diseases. Genome-Wide Association Studies (GWAS) have identified common genetic variants with modest effect sizes, and most identified variants reside in non-coding regions.
Aim: We sought to identify rare variants influencing brain MRI measures in the Framingham Study by performing Whole Genome Sequence (WGS) analyses within the Trans-Omics for Precision Medicine (TOPMed) Program.
Methods: A total of 905, 894 and 672 individuals were included in the WGS analyses of TBV, HPV and WMH. Rank-normalized residuals from mixed effect linear regression models adjusted for sex, age and total intracranial volume were tested for association with individual SNPs while accounting for familial relatedness. Gene-based tests were conducted for rare variants with SKAT or burden test using a sliding-window approach or selection of functional exonic SNPs. Finally, WGS results were compared to GWAS using imputed data from the Haplotype Reference Consortium (~4,000 individuals).
Results: WGS analyses revealed a new genome-wide locus (P≤5x10-8) in 3q24 for HPV (PWGS=2.0x10-9, PGWAS=0.003). Known associations in 12q24 for HPV (PWGS≤2.5x10-3, PGWAS≤4.1x10-8) and in 17q25 for WMH (PWGS≤2.8x10-4, PGWAS≤4.2x10-6) were observed. Gene-based tests using a sliding-window approach detected genome-wide new loci (P≤2.5x10-6) for HPV (3q24) and TBV (17p13) with SKAT and for HPV (4p15, 12q23, 12q24) and TBV (5q23, 9p21) with burden test. The HPV 3q24 locus includes ZIC1, a transcription factor expressed only in human brain with tumor suppressor function and important role in brain development that can transactivate APOE, whose ε4 allele is the major known risk-factor for late-onset AD.
Conclusion: This study reveals intriguing new loci determining brain volumes. Replication is underway to confirm these findings.

Background: Brain MRI measures such as Total Brain Volume (TBV), Hippocampal Volume (HPV) and White Matter Hyperintensities (WMH) are endophenotypes of Alzheimer disease (AD) and vascular injury. Identifying loci that influence these measures may lead to the discovery of new genes and biological mechanisms underlying these diseases. Genome-Wide Association Studies (GWAS) have identified common genetic variants (Minor Allele Frequency ≥ 5%) with modest effect sizes, and most identified variants reside in non-coding regions.
Aim: We sought to identify rare variants influencing TBV, HPV and WMH in the Framingham Study by performing Whole Genome Sequence (WGS) analyses within the Trans-Omics for Precision Medicine (TOPMed) Program.
Methods: A total of 905, 894 and 672 individuals from TOPMed were included in the WGS analyses of TBV, HPV and WMH respectively. Mixed effect linear regression models of brain MRI measures were adjusted for sex, age and total intracranial volume and rank-normalized residuals from these models were tested for association with individual SNPs while taking into account familial relatedness. Gene-based tests were conducted for rare variants with two different methods (SKAT or burden test) using 1) a sliding-window approach or 2) a selection of functional exonic SNPs. Finally, WGS results were compared to GWAS using imputed data from the Haplotype Reference Consortium release 1 (~4,000 genotyped individuals with phenotype data).
Results: WGS analyses revealed at the genome-wide level (P≤5x10-8) a new locus in 3q24 for HPV (PWGS=2.0x10-9, PGWAS=0.003) and suggestive results (P≤10-6) in new regions for HPV (5q35, 8q24, 11p15, 19p13), WMH (11p12) and TBV (4q25). Known associations in 12q24 for HPV (PWGS ≤ 2.5x10-3, PGWAS ≤ 4.1x10-8) and in 17q25 for WMH (PWGS ≤ 2.8x10-4, PGWAS ≤ 4.2x10-6) were observed. Gene-based tests using a sliding-window approach detected genome-wide associations (P≤2.5x10-6) in new loci for HPV (3q24) and TBV (17p13) with the SKAT method and for HPV (4p15, 12q23, 12q24) and TBV (5q23, 9p21) with the burden test. The 3q24 locus associated with HPV includes ZIC1, a transcription factor expressed only in human brain with tumor suppressor function that has an important role in brain development and can transactivate APOE, whose ε4 allele is the major known risk-factor for late-onset AD.
Conclusion: This study reveals intriguing new loci determining brain volumes. Replication is underway to confirm these findings.