Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Figures & data

Table 1.  Differentially methylated loci in peripheral blood mononuclear cells associated with Montreal Cognitive Assessment.

Chr	Position	IlluminaID	Coefficient^†	p-value	Gene name (UCSC)	Gene feature	Relation_to _CpG_island
chr15	83953775	cg26429925	-0.75	4.71E-06	BNC1	TSS1500	Island
chr13	50202570	cg08772163	0.68	8.32E-06	ARL11	TSS200
chr19	44455454	cg03227078	-0.69	8.97E-06	ZNF221	5′-UTR; 1stExon	Island
chr4	183243982	cg18351711	0.93	1.14E-05	ODZ3	TSS1500
chr5	57756024	cg11821403	-0.72	1.28E-05	PLK2	TSS200	Island
chr16	28857989	cg05666372	0.65	2.54E-05	TUFM	TSS1500	Island
chr16	619677	cg06486124	0.68	3.16E-05	PIGQ	TSS1500	Shore
chr2	112939562	cg20313969	-0.88	4.24E-05	FBLN7	Body; Body	Island
chr6	116601353	cg02007388	0.68	4.71E-05	TSPYL1; DSE	TSS200; 1stExon	Shore
chr16	89408076	cg05497216	-0.89	4.75E-05	ANKRD11	5′-UTR	Shore

The most significant DMPs.

^†Standardized regression coefficient.

DMP: Differentially methylated position; TSS: Transcription Start Site; UCSC: University of California, Santa Cruz.

Table 2.  Differentially methylated loci in peripheral blood mononuclear cells associated with Montreal Cognitive Assessment.

Chr	Start	Stop	Probes in DMR	p-value	Sidak-corrected p-value	Gene name (UCSC)	Gene feature	Relation_to _CpG_island	Direction of association with MoCA
chr6	33048253	33048761	10	1.53E-11	2.32E-08	HLA-DPA1; HLA-DPB1	TSS; intron; exon; 5′-UTR; CDS	Island	+
chr2	26624603	26625048	9	1.83E-10	3.16E-07	DRC1	TSS; intron; 5′-UTR; CDS	Island	-
chr1	57110866	57111123	6	1.15E-08	3.44E-05	PRKAA2; LOC101929935	TSS; 5′-UTR; CDS; intron + Exon	Island	-
chr11	15095016	15095179	6	4.14E-08	1.96E-04	CALCB	TSS; Exon; 5′-UTR	Island	-
chr18	25757437	25757711	3	2.73E-07	7.67E-04	CDH2	Intergenic	Island	-
chr19	12936490	12936803	5	3.75E-07	9.21E-04	RTBDN	Intron; UTR3; CDS; exon	Island	-
chr19	58458916	58459359	9	8.59E-07	1.49E-03	ZNF256	TSS; exon; 5′-UTR	Island	-
chr11	70672739	70672987	7	7.12E-07	2.21E-03	SHANK2	Intron	Island	-
chr1	77747373	77747388	3	1.75E-06	8.57E-02	AK5	Intergenic	Island	-
chr5	96038284	96038402	7	2.20E-05	1.34E-01	CAST	Intron + UTR5; TSS + exon	Island	-
chr6	31650834	31651095	9	3.88E-04	6.82E-01	LY6G5C	Intergenic	Island	-

The top eight DMRs with Sidak-corrected p < 0.05 are in bold.

CDS: Coding sequence; DMP: Differentially methylated position; DMR: Differentially methylated region; MoCA: Montreal Cognitive Assessment; TSS: Transcription Start Site; UCSC: University of California, Santa Cruz.

Figure 1.  DNA methylation in peripheral blood mononuclear cells is associated with cognitive and neuroimaging measures.

(A) Manhattan plot of differentially methylated regions (DMRs) associated with Montreal Cognitive Assessment. Red dots indicate the chromosomal location of individual probes within each DMR. The University of California Santa Cruz gene symbols corresponding to DMRs with more than three probes after Sidak correction for multiple testing are assigned to the chromosomal locations. (B) Heatmap of module–trait correlations for the remaining 24 modules, after excluding modules with significant association with the covariates of cell composition, batch, age, gender, smoking and IQ. Shown are the correlations of Montreal Cognitive Assessment, total brain volume, left hippocampal volume, right hippocampal volume, cerebrospinal fluid volume, white matter volume, gray matter volume, fractional anisotropy, mean diffusivity and white matter hyperintensities with each module. For each module–trait pair the upper value is the Pearson correlation coefficient, while the lower (bracketed) value is the correlation p-value. The cell color represents the strength and direction of the correlation. Modules are assigned an arbitrary color by the analysis software according to their size. (C) The correlation between module membership and gene significance for each probe in the ‘yellowgreen’ module.

CSF: Cerebrospinal fluid volume; FA: Fractional anisotropy; GM: Grey matter volume; LHV: Left hippocampal volume; MD: Mean diffusivity; ME: Module eigengene; MoCA: Montreal Cognitive Assessment; RHV: Right hippocampal volume; WM: White matter volume.

Figure 1.  DNA methylation in peripheral blood mononuclear cells is associated with cognitive and neuroimaging measures.

(A) Manhattan plot of differentially methylated regions (DMRs) associated with Montreal Cognitive Assessment. Red dots indicate the chromosomal location of individual probes within each DMR. The UCSC gene symbols corresponding to DMRs with more than three probes after Sidak correction for multiple testing are assigned to the chromosomal locations. (B) Heatmap of module–trait correlations for the remaining 24 modules, after excluding modules with significant association with the covariates of cell composition, batch, age, gender, smoking and IQ. Shown are the correlations of Montreal Cognitive Assessment, total brain volume, left hippocampal volume, right hippocampal volume, cerebrospinal fluid volume, white matter volume, gray matter volume, fractional anisotropy, mean diffusivity and white matter hyperintensities with each module. For each module–trait pair the upper value is the Pearson correlation coefficient, while the lower (bracketed) value is the correlation p-value. The cell color represents the strength and direction of the correlation. Modules are assigned an arbitrary color by the analysis software according to their size. (C) The correlation between module membership and gene significance for each probe in the ‘yellowgreen’ module.

CSF: Cerebrospinal fluid volume; FA: Fractional anisotropy; GM: Grey matter volume; LHV: Left hippocampal volume; MD: Mean diffusivity; ME: Module eigengene; MoCA: Montreal Cognitive Assessment; RHV: Right hippocampal volume; WM: White matter volume.

Figure 1.  DNA methylation in peripheral blood mononuclear cells is associated with cognitive and neuroimaging measures.

(A) Manhattan plot of differentially methylated regions (DMRs) associated with Montreal Cognitive Assessment. Red dots indicate the chromosomal location of individual probes within each DMR. The UCSC gene symbols corresponding to DMRs with more than three probes after Sidak correction for multiple testing are assigned to the chromosomal locations. (B) Heatmap of module–trait correlations for the remaining 24 modules, after excluding modules with significant association with the covariates of cell composition, batch, age, gender, smoking and IQ. Shown are the correlations of Montreal Cognitive Assessment, total brain volume, left hippocampal volume, right hippocampal volume, cerebrospinal fluid volume, white matter volume, gray matter volume, fractional anisotropy, mean diffusivity and white matter hyperintensities with each module. For each module–trait pair the upper value is the Pearson correlation coefficient, while the lower (bracketed) value is the correlation p-value. The cell color represents the strength and direction of the correlation. Modules are assigned an arbitrary color by the analysis software according to their size. (C) The correlation between module membership and gene significance for each probe in the ‘yellowgreen’ module.

CSF: Cerebrospinal fluid volume; FA: Fractional anisotropy; GM: Grey matter volume; LHV: Left hippocampal volume; MD: Mean diffusivity; ME: Module eigengene; MoCA: Montreal Cognitive Assessment; RHV: Right hippocampal volume; WM: White matter volume.