Genome-wide association study of executive function in a multi-ethnic cohort implicates LINC01362: Results from the northern Manhattan study

Cognition is a complex human trait comprised of several domains including executive function. Executive function is an umbrella term that includes clusters of higher-order cognitive abilities such as planning, working memory, processing speed, mental flexibility and the initiation or monitoring of action (Mapstone et al., 2005). Cognitive functions have a significant impact on quality of life, and cognitive impairment is a recognized public health burden (Black et al., 2002). Mental processes that comprise executive function facilitate concentration and planning for future activities, as well as reasoning and problem solving, initiation of action, and efficiently switching between different tasks, among other functions (Diamond et al., 2013). Executive function is influenced by genetic factors, with heritability estimates reported to be between 31% and 63% depending on the tests used (Vasilopoulos et al., 2012; Lee et al., 2012; Swan and Carmelli, 2002). The genetic underpinnings of executive function, however, are largely unknown.

Several genome-wide association studies (GWAS) on executive function have been reported (Jian et al., 2020; Cirulli et al., 2010; Need et al., 2009; Wendel et al., 2021; LeBlanc et al., 2012; Ibrahim-Verbaas et al. 2016; Seshadri et al., 2007), each analyzing different measures of executive function. One of the largest GWAS, conducted in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium, examined participants of European ancestry aged 45 years or older for genetic association with the Trail Making Test Part B, Stroop Interference, and tests of phonemic and semantic fluency (N = 6210-13,454, depending on test) (Ibrahim-Verbaas et al. 2016). This study identified suggestive (p < 1.0 × 10-6) associations on chromosomes 1p31.3, 8q24.3, 9q21.33 and 18q12.3, although none were genome-wide significant. The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) reported one of the few GWAS focusing on non-European individuals. This study examined several measures of cognitive function including the Word Fluency Test (WFT), a measure of executive function and processing speed, in middle aged Hispanics/Latinos (mean age = 55, N = 7606). This study found 2 loci at 3p14.1and 6p21.32 to be significantly associated with the WFT (p < 5.0 × 10-8), although neither replicated in the CHARGE consortium (Jian et al., 2020). Additional significantly associated loci identified through previous studies include a region on chromosome 5 associated with performance change-over-time for trail making test part B (Wendel et al., 2021), and a region on chromosome 15 associated with executive functioning (LeBlanc et al., 2012).

Previous GWAS have either analyzed several individual tests of executive function, therefore surrendering statistical power to multiple testing correction, or have been limited to one individual test which reflects only 1 aspect of the executive function domain. A composite measure of executive function has been proposed to identify true cognitive impairment via capturing several aspects of this multidimensional phenotype. Additionally, it is well acknowledged that risk genes and variants for complex traits may be race- and ethnic-specific. However, most GWAS of cognitive traits have focused on individuals of European descent (Cirulli et al., 2010; Need et al., 2009; Wendel et al., 2021; LeBlanc et al., 2012; Ibrahim-Verbaas et al. 2016; Seshadri et al., 2007). Therefore, we performed a GWAS on a composite measure of executive function using data from a racially and ethnically diverse cohort to help close the racial and ethnic diversity gap in cognitive neuroscience research (Dotson and Duarte, 2020).

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