EEG delta power in NREM sleep after SD is associated with Kif16b and Wrn.

(A) NREM sleep EEG spectra in the first 3 h after SD (ZT6–9) for the 2 BXD lines that displayed the lowest and highest EEG activity in the fast delta frequency band (2.5–4.25 Hz, δ2; top, see panel E) and for the 2 BXD lines that displayed the smallest and largest increase (or gain) in EEG power in the slow delta band (1.0–2.25 Hz, δ1; bottom, see panel E). Spectra were “1/f-corrected” (and therefore not directly comparable to the values in panel E) for better visualization of activity in higher frequency bands (theta [5–9 Hz, θ], sigma [11–16 Hz, σ], beta [18–30 Hz, β], and slow [32–55 Hz, γ1] and fast gamma [55–80 Hz, γ2]). Subsequent analyses were performed without this correction. (B) QTL mapping and prioritization for δ2 power identified a significant association on chromosome 2 and Kif16b in cortex as top-ranked gene (top). For the δ1 increase after SD, we obtained a suggestive QTL on chromosome 8 and a significant prioritization score for the DNA-helicase Wrn. (C) Hiveplot visualization of network connections for the δ1 and δ2 power after SD (top-left panels) and the SD-induced increase in δ1 and δ2 power over baseline (bottom-left panels). Note the marked differences in the networks and QTLs regulating the expression of these 2 delta bands. Right hiveplots highlight Kif16b in the δ2 power–associated network (top), and Wrn in the network associated with the δ1 increase (bottom). Only Kif16b expression in the cortex was linked to the chromosome 2 cis-eQTL and was not associated with any metabolite. Wrn expression was significantly linked to the chromosome 8 cis-eQTL and to the long phosphatidylcholine, PC-ae-C38:5. (D) Kif16b is highly significantly down-regulated in cortex (left), while it remains unchanged in liver after SD (p = 0.15; not shown). Also, Wrn expression was strongly down-regulated by SD in cortex (right) and only marginally so, albeit significantly, in liver (p = 0.02; not shown). (E) Strain distribution patterns. BXD lines carrying a B6-allele on the chromosome 2–associated region showed higher δ2 power after SD (left) and a significantly higher Kif16b expression (p = 1.3e−15; second to left) than D2-allele carriers. D2-allele carriers of the chromosome 8–associated region showed a larger δ1 increase after SD (second to right) as well as a significantly larger decrease in Wrn expression after SD (right) than B6-allele carriers. For color-coding of genotypes, see Fig 4. CPM, counts per million; Ctr, control; EEG, electroencephalography; eQTL, expression quantitative trait locus; FDR, false discovery rate; Kif16b, Kinesin family member 16B; NREM, non-REM; PC-ae, phosphatidylcholine acyl-alkyl; QTL, quantitative trait locus; SD, sleep deprivation; Wrn, Werner syndrome RecQ like helicase; ZT, zeitgeber time