Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

K. Nho; J. J. Corneveaux; S. Kim; H. Lin; S. L. Risacher; L. Shen; S. Swaminathan; V. K. Ramanan; Y. Liu; T. Foroud; M. H. Inlow; A. L. Siniard; R. A. Reiman; P. S. Aisen; R. C. Petersen; R. C. Green; C. R. Jack; M. W. Weiner; C. T. Baldwin; K. Lunetta; L. A. Farrer; S. J. Furney; S. Lovestone; A. Simmons; P. Mecocci; B. Vellas; M. Tsolaki; I. Kloszewska; H. Soininen; B. C. McDonald; M. R. Farlow; B. Ghetti; M. J. Huentelman; A. J. Saykin; MIRAGE Study; AddNeuroMed Consortium; Indiana Memory Aging Study; ADNI

doi:10.1038/mp.2013.24

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

K. Nho, J. J. Corneveaux, S. Kim, H. Lin, S. L. Risacher, L. Shen, S. Swaminathan, V. K. Ramanan, Y. Liu, T. Foroud, M. H. Inlow, A. L. Siniard, R. A. Reiman, P. S. Aisen, R. C. Petersen, R. C. Green, C. R. Jack, M. W. Weiner, C. T. Baldwin, K. LunettaL. A. Farrer, S. J. Furney, S. Lovestone, A. Simmons, P. Mecocci, B. Vellas, M. Tsolaki, I. Kloszewska, H. Soininen, B. C. McDonald, M. R. Farlow, B. Ghetti, M. J. Huentelman, A. J. Saykin^*, MIRAGE Study, AddNeuroMed Consortium, Indiana Memory Aging Study, ADNI

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) epsilon 4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE epsilon 3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE epsilon 3/epsilon 3 group (N = 315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE epsilon 3/epsilon 3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE epsilon 3/epsilon 3 individuals (N = 923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Original language	English
Article number	N/A
Pages (from-to)	781-787
Number of pages	7
Journal	Molecular Psychiatry
Volume	18
Issue number	7
DOIs	https://doi.org/10.1038/mp.2013.24
Publication status	Published - Jul 2013

Keywords

ADNI
CARD10
imaging genetics
mild cognitive impairment
PARP1
whole-exome sequencing
GENOME-WIDE ASSOCIATION
NF-KAPPA-B
ONSET ALZHEIMER-DISEASE
POLY(ADP-RIBOSE) POLYMERASE-1
APOLIPOPROTEIN-E
AMYLOID-BETA
POLYADP-RIBOSYLATION
COMPLEX DISEASES
COMMON VARIANTS
FAMILY MEMBER
Acknowledged-BRC
Acknowledged-BRC-13/14

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10.1038/mp.2013.24

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Nho, K., Corneveaux, J. J., Kim, S., Lin, H., Risacher, S. L., Shen, L., Swaminathan, S., Ramanan, V. K., Liu, Y., Foroud, T., Inlow, M. H., Siniard, A. L., Reiman, R. A., Aisen, P. S., Petersen, R. C., Green, R. C., Jack, C. R., Weiner, M. W., Baldwin, C. T., ... ADNI (2013). Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment. Molecular Psychiatry, 18(7), 781-787. Article N/A. https://doi.org/10.1038/mp.2013.24

@article{258d0c9feac6463b9596e653ae5260e6,

title = "Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment",

abstract = "Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) epsilon 4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE epsilon 3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE epsilon 3/epsilon 3 group (N = 315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE epsilon 3/epsilon 3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE epsilon 3/epsilon 3 individuals (N = 923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.",

keywords = "ADNI, CARD10, imaging genetics, mild cognitive impairment, PARP1, whole-exome sequencing, GENOME-WIDE ASSOCIATION, NF-KAPPA-B, ONSET ALZHEIMER-DISEASE, POLY(ADP-RIBOSE) POLYMERASE-1, APOLIPOPROTEIN-E, AMYLOID-BETA, POLYADP-RIBOSYLATION, COMPLEX DISEASES, COMMON VARIANTS, FAMILY MEMBER, Acknowledged-BRC, Acknowledged-BRC-13/14",

author = "K. Nho and Corneveaux, {J. J.} and S. Kim and H. Lin and Risacher, {S. L.} and L. Shen and S. Swaminathan and Ramanan, {V. K.} and Y. Liu and T. Foroud and Inlow, {M. H.} and Siniard, {A. L.} and Reiman, {R. A.} and Aisen, {P. S.} and Petersen, {R. C.} and Green, {R. C.} and Jack, {C. R.} and Weiner, {M. W.} and Baldwin, {C. T.} and K. Lunetta and Farrer, {L. A.} and Furney, {S. J.} and S. Lovestone and A. Simmons and P. Mecocci and B. Vellas and M. Tsolaki and I. Kloszewska and H. Soininen and McDonald, {B. C.} and Farlow, {M. R.} and B. Ghetti and Huentelman, {M. J.} and Saykin, {A. J.} and {MIRAGE Study} and {AddNeuroMed Consortium} and {Indiana Memory Aging Study} and ADNI",

year = "2013",

month = jul,

doi = "10.1038/mp.2013.24",

language = "English",

volume = "18",

pages = "781--787",

journal = "Molecular Psychiatry",

issn = "1359-4184",

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Nho, K, Corneveaux, JJ, Kim, S, Lin, H, Risacher, SL, Shen, L, Swaminathan, S, Ramanan, VK, Liu, Y, Foroud, T, Inlow, MH, Siniard, AL, Reiman, RA, Aisen, PS, Petersen, RC, Green, RC, Jack, CR, Weiner, MW, Baldwin, CT, Lunetta, K, Farrer, LA, Furney, SJ , Lovestone, S , Simmons, A, Mecocci, P, Vellas, B, Tsolaki, M, Kloszewska, I, Soininen, H, McDonald, BC, Farlow, MR, Ghetti, B, Huentelman, MJ, Saykin, AJ, MIRAGE Study, AddNeuroMed Consortium, Indiana Memory Aging Study & ADNI 2013, 'Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment', Molecular Psychiatry, vol. 18, no. 7, N/A, pp. 781-787. https://doi.org/10.1038/mp.2013.24

TY - JOUR

T1 - Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

AU - Nho, K.

AU - Corneveaux, J. J.

AU - Kim, S.

AU - Lin, H.

AU - Risacher, S. L.

AU - Shen, L.

AU - Swaminathan, S.

AU - Ramanan, V. K.

AU - Liu, Y.

AU - Foroud, T.

AU - Inlow, M. H.

AU - Siniard, A. L.

AU - Reiman, R. A.

AU - Aisen, P. S.

AU - Petersen, R. C.

AU - Green, R. C.

AU - Jack, C. R.

AU - Weiner, M. W.

AU - Baldwin, C. T.

AU - Lunetta, K.

AU - Farrer, L. A.

AU - Furney, S. J.

AU - Lovestone, S.

AU - Simmons, A.

AU - Mecocci, P.

AU - Vellas, B.

AU - Tsolaki, M.

AU - Kloszewska, I.

AU - Soininen, H.

AU - McDonald, B. C.

AU - Farlow, M. R.

AU - Ghetti, B.

AU - Huentelman, M. J.

AU - Saykin, A. J.

AU - MIRAGE Study

AU - AddNeuroMed Consortium

AU - Indiana Memory Aging Study

AU - ADNI

PY - 2013/7

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N2 - Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) epsilon 4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE epsilon 3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE epsilon 3/epsilon 3 group (N = 315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE epsilon 3/epsilon 3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE epsilon 3/epsilon 3 individuals (N = 923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

AB - Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) epsilon 4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE epsilon 3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE epsilon 3/epsilon 3 group (N = 315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE epsilon 3/epsilon 3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE epsilon 3/epsilon 3 individuals (N = 923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

KW - ADNI

KW - CARD10

KW - imaging genetics

KW - mild cognitive impairment

KW - PARP1

KW - whole-exome sequencing

KW - GENOME-WIDE ASSOCIATION

KW - NF-KAPPA-B

KW - ONSET ALZHEIMER-DISEASE

KW - POLY(ADP-RIBOSE) POLYMERASE-1

KW - APOLIPOPROTEIN-E

KW - AMYLOID-BETA

KW - POLYADP-RIBOSYLATION

KW - COMPLEX DISEASES

KW - COMMON VARIANTS

KW - FAMILY MEMBER

KW - Acknowledged-BRC

KW - Acknowledged-BRC-13/14

U2 - 10.1038/mp.2013.24

DO - 10.1038/mp.2013.24

M3 - Article

SN - 1359-4184

VL - 18

SP - 781

EP - 787

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 7

M1 - N/A

ER -

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

Abstract

Keywords

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