A Phenome-Wide Association Study (PheWAS) of Late Onset Alzheimer Disease Genetic Risk in Children of European Ancestry at Middle Childhood: Results from the ABCD Study

Abstract

Genetic risk for Late Onset Alzheimer Disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, whether these and other associations are present during childhood remains unclear. Using data from 5556 genomically-confirmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive Development^SM Study (ABCD Study®), our phenome-wide association study estimating associations between four indices of genetic risk for late-onset AD (i.e., AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (AD_PRS-APOE), and an interaction between AD_PRS-APOE and APOE genotype) and 1687 psychosocial, behavioral, and neural phenotypes revealed no significant associations after correction for multiple testing (all ps > 0.0002; all p_fdr > 0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect.

Keywords: APOE; Alzheimer disease; Imaging; Middle childhood; Phenome-wide association study; Polygenic risk scores.

Fig. 1

PheWAS Results for Non-imaging Phenotypes. Association between four genetic risk indices and cognitive, behavioral, and psychosocial phenotypes: A polygenic risk score (PRS) derived from the largest AD GWAS, B APOE rs429358 risk alleles, C a PRS that excludes the APOE4 region, and D the moderation of the PRS that excludes the APOE4 region by APOE4. Key for figure: 1a: ksads_10_324_p = “Symptom—Difficulty controlling worries Present,” ksads_10_322_p = “Symptom—Worry associated with defined symptom(s) Present,” devhx_19b_p = “At approximately what age (number of months) was he/she FIRST able to sit without assistance?,” and ksads_10_47_p = “Symptom—Worrying has lasted at least 6 months Present.” Key for Fig. 1B: asr_q07_p = “I brag”, devhx_19b_p = “At approximately what age (number of months) was he/she FIRST able to sit without assistance?,” parent_monitor_q4_y = “How often do you talk to your parent or guardian about your plans for the coming day, such as your plans about what will happen at school or what you are going to do with friends?,” and ksads_11_346_p = “Symptom—Impairment in functioning due to compulsions Past.” Key for Fig. 1C: medhx_6d = “Has he/she ever been to a doctor, a nurse, nurse practitioner, the emergency room or a clinic because Stitches,” cbcl_q11_p = “Clings to adults or too dependent,” asr_q14_p = “I cry a lot,” and devhx_14a3_p = “Did he/she have any of the following complications at birth? Blue at birth? Key for Fig. 1D: famhx_ss_matant1_prob_nrv_p = “maternal aunt 1 nerves/nervous breakdown problem,” kbi_p_c_spec_serv___7 = “Does your child receive special services at school?,” devhx_19b_p = “At approximately what age (number of months) was he/she FIRST able to sit without assistance?,” asr_q125_p = “In the past 6 months, on how many days were you drunk?,” and medhx_6i = “Has he/she ever been to a doctor, a nurse, nurse practitioner, the emergency room or a clinic because of a head injury.”