Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Abstract

INTRODUCTIONLate‐onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long‐Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.METHODSWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub‐sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.RESULTSWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10−9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DISCUSSIONMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.Highlights Long‐Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

The Alzheimer's Biomarker Consortium–Down Syndrome (ABC‐DS): A 10‐year report

“…While their functional roles need to be further characterized, some novel genes include four novel loci associated with amyloid β peptides ( PFKFB3, DLX3/PICART1 ; LINC01941/GYPC and PDE4D ) and four loci with tau phenotypes ( TUBAP, CTNND2 , LSTN2, and JHY ). 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD).…”

“… 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD). For example, Gorijala et al 54 constructed polygenic risk scores (PRS) using the AD genetic risk variants from the neurotypical population, and found that the PRS for AD was not associated with familial early‐onset AD (EOAD) and DS‐AD, but was associated with memory scores in DS, independent of APOE .…”

The Alzheimer's Biomarker Consortium–Down Syndrome (ABC‐DS): A 10‐year report

“…While their functional roles need to be further characterized, some novel genes include four novel loci associated with amyloid β peptides ( PFKFB3, DLX3/PICART1 ; LINC01941/GYPC and PDE4D ) and four loci with tau phenotypes ( TUBAP, CTNND2 , LSTN2, and JHY ). 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD).…”

“… 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD). For example, Gorijala et al 54 constructed polygenic risk scores (PRS) using the AD genetic risk variants from the neurotypical population, and found that the PRS for AD was not associated with familial early‐onset AD (EOAD) and DS‐AD, but was associated with memory scores in DS, independent of APOE .…”

Association between chronic stress and the epigenome: Exploration of psychological and biological stress

“…A CpG site within the microtubule associated scaffold protein 2 ( MTUS2 ) gene had the strongest negative association with psychological stress. Differential DNAm in the MTUS2 gene has previously been found in blood samples from Parkinson’s disease patients compared to healthy controls [ 64 ] and genomic studies implicate MTUS2 late-onset Alzheimer’s disease [ 65 ]. Studies of acute and chronic stress in mice suggest that differential DNAm within the Mtus2 gene may serve as an “epigenetic primer” to stress exposure and its neurobiological and behavioral consequences [ 66 ].…”

Alectinib efficacy in advanced lung adenocarcinoma with coexistence of a novel ALK-MTUS2 and STRN3-ALK double fusion: A case report and literature review

“…In an NGS-based study of breast cancer genomics, MTUS2 emerged as a potential driver of the disease ( 11 ). Additionally, MTUS2 may be a potential therapeutic target for Alzheimer's disease ( 12 ). To date, and to the best of our knowledge, the ALK-MTUS2 fusion in NSCLC has been unreported.…”

The Alzheimer's Biomarker Consortium–Down Syndrome (ABC‐DS): A 10‐year report

“…While their functional roles need to be further characterized, some novel genes include four novel loci associated with amyloid β peptides ( PFKFB3, DLX3/PICART1 ; LINC01941/GYPC and PDE4D ) and four loci with tau phenotypes ( TUBAP, CTNND2 , LSTN2, and JHY ). 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD).…”

“… 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD). For example, Gorijala et al 54 constructed polygenic risk scores (PRS) using the AD genetic risk variants from the neurotypical population, and found that the PRS for AD was not associated with familial early‐onset AD (EOAD) and DS‐AD, but was associated with memory scores in DS, independent of APOE .…”

Association between chronic stress and the epigenome: Exploration of psychological and biological stress

“…A CpG site within the microtubule associated scaffold protein 2 ( MTUS2 ) gene had the strongest negative association with psychological stress. Differential DNAm in the MTUS2 gene has previously been found in blood samples from Parkinson’s disease patients compared to healthy controls [ 64 ] and genomic studies implicate MTUS2 late-onset Alzheimer’s disease [ 65 ]. Studies of acute and chronic stress in mice suggest that differential DNAm within the Mtus2 gene may serve as an “epigenetic primer” to stress exposure and its neurobiological and behavioral consequences [ 66 ].…”

Alectinib efficacy in advanced lung adenocarcinoma with coexistence of a novel ALK-MTUS2 and STRN3-ALK double fusion: A case report and literature review

“…In an NGS-based study of breast cancer genomics, MTUS2 emerged as a potential driver of the disease ( 11 ). Additionally, MTUS2 may be a potential therapeutic target for Alzheimer's disease ( 12 ). To date, and to the best of our knowledge, the ALK-MTUS2 fusion in NSCLC has been unreported.…”

The Alzheimer's Biomarker Consortium–Down Syndrome (ABC‐DS): A 10‐year report

“…While their functional roles need to be further characterized, some novel genes include four novel loci associated with amyloid β peptides ( PFKFB3, DLX3/PICART1 ; LINC01941/GYPC and PDE4D ) and four loci with tau phenotypes ( TUBAP, CTNND2 , LSTN2, and JHY ). 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD).…”

“… 53 Furthermore, ABC‐DS participants, along with other at risk cohorts, showed their relevance in human AD modeling by confirming a novel gene, MTUS2 , identified from a neurotypical healthy aging cohort. 53 In addition, our investigators have compared AD progress in DS with that of other at‐risk populations, namely autosomal dominant Alzheimer's disease (ADAD). For example, Gorijala et al 54 constructed polygenic risk scores (PRS) using the AD genetic risk variants from the neurotypical population, and found that the PRS for AD was not associated with familial early‐onset AD (EOAD) and DS‐AD, but was associated with memory scores in DS, independent of APOE .…”

Association between chronic stress and the epigenome: Exploration of psychological and biological stress

“…A CpG site within the microtubule associated scaffold protein 2 ( MTUS2 ) gene had the strongest negative association with psychological stress. Differential DNAm in the MTUS2 gene has previously been found in blood samples from Parkinson’s disease patients compared to healthy controls [ 64 ] and genomic studies implicate MTUS2 late-onset Alzheimer’s disease [ 65 ]. Studies of acute and chronic stress in mice suggest that differential DNAm within the Mtus2 gene may serve as an “epigenetic primer” to stress exposure and its neurobiological and behavioral consequences [ 66 ].…”

Alectinib efficacy in advanced lung adenocarcinoma with coexistence of a novel ALK-MTUS2 and STRN3-ALK double fusion: A case report and literature review

“…In an NGS-based study of breast cancer genomics, MTUS2 emerged as a potential driver of the disease ( 11 ). Additionally, MTUS2 may be a potential therapeutic target for Alzheimer's disease ( 12 ). To date, and to the best of our knowledge, the ALK-MTUS2 fusion in NSCLC has been unreported.…”