**1. Introduction**

Sarcopenia refers to the progressive deterioration in skeletal muscle mass, strength and physical function with advancing age [1]. The simultaneous presence of low muscle strength, muscle mass and/or physical function forms the diagnostic basis of the recommendations from the European Working Group on Sarcopenia in Older People [2]. These criteria are strong predictors of a multitude of adverse health outcomes, such as cardiovascular disease [3], functional disability [4], fall incidence [5], hospitalisation [6], stroke [7] and mortality [8]. Up to 10% of individuals aged 60–69 years are affected by sarcopenia, with this proportion rising considerably to 40% for adults over 80 years of age [9,10]. The fundamental loss of independence and susceptibility to additional diseases caused by sarcopenia also places a significant burden on public health systems worldwide. This burden is anticipated to grow considerably in coming decades, in line with increases in longevity and the consequent rise in

the proportion of elderly [11]. Thus, the consequences of age-related muscle deterioration will become increasingly relevant globally.

While sarcopenia is generally more prevalent among individuals over the age of 60, strong evidence suggests that pronounced changes in muscle tissue begin from around 50 years of age [12]. From this age, muscle mass and strength begin to deteriorate at an annual rate of 1–2% and 1.5–5% respectively [12–14]. Developing an understanding of why and how skeletal muscle deteriorates from this age will be critical to reducing the burden of sarcopenia for patients as well as public health systems.

Currently, it is known that inter-individual variation in muscle phenotypes may be attributed to genetic factors, environmental factors and/or, gene-environment interactions [15,16]. While environmental factors such as physical activity, protein intake [17], sleep quality [18], smoking status [15] and alcohol consumption [19] have been shown to affect muscle phenotypes, heritability studies have highlighted the importance of genetic factors in determining inter-individual variability in skeletal muscle traits [20,21]. These studies have found that genetic factors account for 46–76% and 32–67% of fat-free mass (FFM) and muscle strength variability, respectively [20,21]. Additional longitudinal studies have observed heritability estimates of 64% for change in muscle strength with advancing age [22]. However, while the overall heritability of skeletal muscle phenotypes is well established, the genetic mechanisms underpinning this heritability remain unclear.

Thus, developing a deeper understanding of genetic associations underpinning skeletal muscle phenotypes is of paramount importance in the development of effective treatment interventions to manage age-related changes in muscle structure and function. Furthermore, understanding the genetic mechanisms regulating muscle accrual and loss will help facilitate early screening for susceptibility to sarcopenia, which could allow for preventative measures to be implemented prior to predicted muscle degradation.

Therefore, the purpose of this systematic review was to identify and synthesize the genetic variants associated with muscle phenotypes relevant to sarcopenia in humans.

#### **2. Materials and Methods**

Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [23].

#### *2.1. Literature Search and Eligibility Criteria*

#### 2.1.1. Inclusion and Exclusion Criteria

To be included in this review, studies had to meet the following criteria:


#### 2.1.2. Search Strategy

A systematic literature search of three online databases, PubMed, EMBASE and Web of Science, was conducted on 18 March 2019, for the period between January 2004 and March 2019. This time limit ensured the inclusion of the most pertinent literature. Search terms were selected based off the PEO framework and combined using Boolean operators ("AND", "OR"). Filters were used to limit results to those using human subjects, written in the English language and published within the desired time-frame. The search strategy used was as follows: ("ageing" OR "aged" OR "elderly" OR "older persons" OR "community dwelling") AND ("sarcopenia" OR "skeletal muscle" OR "muscle

phenotype" OR "muscle mass" OR "muscle atrophy" OR "muscle strength" OR "grip strength" OR "physical performance" OR "muscle quality" OR "lean mass") AND ("single nucleotide polymorphism" OR "genetic polymorphism" OR "allele" OR "genetic variation" OR "gene variant" OR "mutation" OR "genes" OR "chromosome" OR "genetic predisposition" OR "genetic susceptibility") AND ("genetic association studies" OR "genome-wide association study" OR "GWAS" OR "candidate gene study" OR "genotype" OR "haplotype" OR "heritability"). The scope of the online search was further expanded by assessing bibliographic references of the eligible full text articles for relevant studies.

#### *2.2. Study Selection and Data Extraction*

Following the removal of duplicates, titles and abstracts were screened for relevance to the scope of this review. To determine inclusion in this review, the full text of every potentially relevant article was scrutinised for overall content and compliance with the eligibility criteria outlined above. The following data were extracted from each eligible article: authors, year of publication, study design, studied population (number, ethnicity, nationality, sex), gene name, polymorphism, muscle phenotype, main findings of the study.

#### *2.3. Phenotypes*

Phenotypic outcomes included in this systematic review were skeletal muscle mass, muscle strength, physical function and sarcopenia prevalence.
