Self-reported neurocognitive complaints in the Swiss HIV Cohort Study: a viral genome-wide association study
Authors: Zeeb Marius , Pasin Chloé , Cavassini Matthias , Bieler-Aeschlimann Mélanie , Frischknecht Paul , Kusejko Katharina , Fellay Jacques , Blanquart François , Metzner Karin J , Neumann Kathrin , Jörimann Lisa , Tschumi Jasmin , Bernasconi Enos , Huber Michael , Kovari Helen , Leuzinger Karoline , Notter Julia , Perreau Matthieu , Rauch Andri , Ramette Alban , Stöckle Marcel , Yerly Sabine , Günthard Huldrych F , Kouyos Roger D ,   the Swiss HIV Cohort Study, Abela Irene , Aebi-Popp Karoline , Anagnostopoulos Alexia , Battegay Manuel , Bernasconi Enos , Braun Dominique L , Bucher Heiner C , Calmy Alexandra , Cavassini Matthias , Ciuffi Angela , Dollenmaier Günther , Egger Matthias , Elzi Luigia , Fehr Jan , Fellay Jacques , Furrer Hansjakob , Fux Christoph A , Günthard Huldrych F , Hachfeld Anna , Haerry David , Hasse Barbara , Hirsch Hans H , Hoffmann Matthias , Hösli Irene , Huber Michael , Jackson-Perry David , Kahlert Christian R , Keiser Olivia , Klimkait Thomas , Kouyos Roger D , Kovari Helen , Kusejko Katharina , Labhardt Niklaus , Leuzinger Karoline , Martinez de Tejada Begona , Marzolini Catia , Metzner Karin J , Müller Nicolas , Nemeth Johannes , Nicca Dunja , Notter Julia , Paioni Paolo , Pantaleo Giuseppe , Perreau Matthieu , Rauch Andri , Salazar-Vizcaya Luisa , Schmid Patrick , Speck Roberto , Stöckle Marcel , Tarr Philip , Trkola Alexandra , Wandeler Gilles , Weisser Maja , Yerly Sabine 
Published: May 2024

Abstract
People with HIV may report neurocognitive complaints, with or without associated neurocognitive impairment, varying between individuals and populations. While the HIV genome could play a major role, large systematic viral genome-wide screens to date are lacking. The Swiss HIV Cohort Study biannually enquires neurocognitive complaints. We quantified broad-sense heritability estimates using partial ‘pol’ sequences from the Swiss HIV Cohort Study resistance database and performed a viral near full-length genome-wide association study for the longitudinal area under the curve of neurocognitive complaints. We performed all analysis (i) restricted to HIV Subtype B and (ii) including all HIV subtypes. From 8547 people with HIV with neurocognitive complaints, we obtained 6966 partial ‘pol’ sequences and 2334 near full-length HIV sequences. Broad-sense heritability estimates for presence of memory loss complaints ranged between 1% and 17% (Subtype B restricted 1–22%) and increased with the stringency of the phylogenetic distance thresholds. The genome-wide association study revealed one amino acid (Env L641E), after adjusting for multiple testing, positively associated with memory loss complaints (P = 4.3 * 10−6). Other identified mutations, while insignificant after adjusting for multiple testing, were reported in other smaller studies (Tat T64N, Env *291S). We present the first HIV genome-wide association study analysis of neurocognitive complaints and report a first estimate for the heritability of neurocognitive complaints through HIV. Moreover, we could identify one mutation significantly associated with the presence of memory loss complaints. Our findings indicate that neurocognitive complaints are polygenetic and highlight advantages of a whole genome approach for pathogenicity determination.