Pervasive biases in proxy GWAS based on parental history of Alzheimer’s disease

Wu, Yuchang; Sun, Zhongxuan; Zheng, Qinwen; Miao, Jiacheng; Dorn, Stephen; Mukherjee, Shubhabrata; Fletcher, Jason M.; Lu, Qiongshi

doi:10.1101/2023.10.13.562272

Cited by 6 publications

(7 citation statements)

References 54 publications

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“…The average life expectancy for a man born in 1920 was 61.77 years compared with 69.22 years for women . One confounding factor for our paternal history results may be that women live longer than men, and many men at this time period did not live long enough to develop late-onset cognitive impairment …”

Section: Discussionmentioning

confidence: 88%

“…13 Other sociological factors to consider include educational and occupational attainment. 28,29 Though results are inconclusive, these factors have been associated with cognitive reserve, and subsequently, reduced AD risk. [30][31][32] During the relevant time period (circa 1940), women were less likely to have access to reserve contributors such as education and occupational complexity.…”

Section: Discussionmentioning

confidence: 99%

“…Other sociological factors to consider include educational and occupational attainment . Though results are inconclusive, these factors have been associated with cognitive reserve, and subsequently, reduced AD risk .…”

Section: Discussionmentioning

confidence: 99%

“…First, parental history was selfreported which may be affected by recall and/or participation bias. 28 Additionally, the primary definition of parental history used in this study was, dementia or significant memory impairment, which may have captured non-AD causes of cognitive decline. The A4 study did not collect the data on the etiology of parental dementia other than AD.…”

Section: Limitationsmentioning

confidence: 99%

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Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

Seto,

Hohman,

Mormino

et al. 2024

JAMA Neurol

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ImportanceStudies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes.ObjectiveTo characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults.Design, Setting, and ParticipantsThis cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded.Main Outcomes and MeasuresDemographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite.ResultsOf 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10−5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10−5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10−5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10−5). Paternal history of early-onset memory impairment (age &lt;65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10−6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition.Conclusions and RelevanceIn this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

See 2 more Smart Citations

Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

Seto,

Hohman,

Mormino

et al. 2024

JAMA Neurol

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“…While cognitive decline has been associated with reduced structural connectivity 56,157 , and cognitive resilience with increased connectivity 158 , in mild cognitive impairment, Alzheimer's disease and/or aging, the relationship between structural connectivity and cognition in healthy individuals after accounting for age has been less well-studied. Note that the Alzheimer's disease GWAS we used included proxy cases for Alzheimer's disease and related dementias, which increases power but can also lead to bias in genetic epidemiological analysis 159 .…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of the structural connectome

Wainberg,

Forde,

Mansour

et al. 2024

Nat Commun

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Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these connections remains unclear. We perform genome-wide association studies of 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography of 26,333 UK Biobank participants, each representing the density of myelinated connections within or between a pair of cortical networks, subcortical structures or cortical hemispheres. We identify 30 independent genome-wide significant variants after Bonferroni correction for the number of measures studied (126 variants at nominal genome-wide significance) implicating genes involved in myelination (SEMA3A), neurite elongation and guidance (NUAK1, STRN, DPYSL2, EPHA3, SEMA3A, HGF, SHTN1), neural cell proliferation and differentiation (GMNC, CELF4, HGF), neuronal migration (CCDC88C), cytoskeletal organization (CTTNBP2, MAPT, DAAM1, MYO16, PLEC), and brain metal transport (SLC39A8). These variants have four broad patterns of spatial association with structural connectivity: some have disproportionately strong associations with corticothalamic connectivity, interhemispheric connectivity, or both, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1 percent of common variants estimated to have non-zero effects on each measure, and exhibited signatures of negative selection. Structural connectivity measures have significant genetic correlations with a variety of neuropsychiatric and cognitive traits, indicating that connectivity-altering variants tend to influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes (as well as microglia, inhibitory neurons and astrocytes) and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. Our results indicate pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, and support the relevance of this genetic control to healthy brain function.

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Bidirectional two-sample Mendelian randomization analyses support causal relationships between structural and diffusion imaging-derived phenotypes and the risk of major neurodegenerative diseases

Wang,

Yang,

et al. 2024

Transl Psychiatry

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Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer’s disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.

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Pervasive biases in proxy GWAS based on parental history of Alzheimer’s disease

Cited by 6 publications

References 54 publications

Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

Genetic architecture of the structural connectome

Bidirectional two-sample Mendelian randomization analyses support causal relationships between structural and diffusion imaging-derived phenotypes and the risk of major neurodegenerative diseases

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