*2.4. Quality Assessment*

The quality and risk of bias of the included studies were assessed using the Quality of Genetic Association Studies (Q-Genie) tool [24]. The Q-Genie tool consists of 11 items that cover the following areas: "rationale for study", "selection and definition of outcome of interest", "selection and comparability of comparison groups", "technical classification of the exposure", "non-technical classification of the exposure", "other source of bias", "sample size and power", "a priori planning of analysis", "statistical methods and control for confounding", "testing of assumptions and inferences for genetic analysis" and "appropriateness of inferences drawn from results". Each area was rated using a 7-point Likert scale ("1 = poor"; "2", "3 = good"; "4", "5 = very good"; "6", "7 = excellent"). The overall quality of the included articles was classified by collating the scores for each theme. Studies with control groups were classified as "poor quality" if the score was ≤ 35, "moderate quality" if the score was > 35 and ≤ 45, and "good quality" if the score was > 45. For studies without control groups, scoring ≤ 32, > 32 and ≤ 40, and > 40 reflected classifications of "poor quality", "moderate quality" and "good quality", respectively.

#### **3. Results**

#### *3.1. Search Strategy*

The systematic search of the online databases identified 771 papers. Following the addition of filters, removal of duplicates and screening for eligibility, 48 studies remained. Six additional articles were retrieved through the manual search of reference lists, leaving a total of 54 articles to be included in this systematic review. Figure 1 highlights the identification and selection process in accordance with the PRISMA statement.

**Figure 1.** PRISMA flow chart presenting the identification and selection process of articles.

### *3.2. Quality Assessment*

A detailed quality classification for each article is displayed in Table 1. Studies scored between 33 and 50 in the Q-Genie checklist. For studies with control groups (*n* = 12), five were classified as "moderate quality" and seven as "good quality". For non-control group studies (*n* = 42), 17 were classified as "moderate quality" and 25 as "good quality".


**Table 1.** Q-Genie quality assessment scores for the included studies.

**Table 1.** *Cont*.


Items: 1: Rationale for study, 2: Selection and definition of outcome of interest, 3: Selection and comparability of comparison groups, 4: Technical classification of the exposure, 5: Non-technical classification of the exposure, 6: Other sources of bias, 7: Sample size and power, 8: A priori planning of analysis, 9: Statistical methods and control for confounding, 10: Testing of assumptions and inferences for genetic analyses, 11: Appropriateness of inferences drawn from results. Scoring: 1 to 7, 1 being poor and 7 being excellent. N/A: not applicable.

#### *3.3. Study and Subject Characteristics*

Of the 54 studies included in this systematic review, 35 were cross sectional studies while the remaining 19 were longitudinal. A comprehensive description of the characteristics of the cross-sectional studies are presented in Table 2. Of the longitudinal studies, 11 were intervention studies while 8 were observational follow-up studies. The average intervention length was 21.3 weeks (range 10–72 weeks) while the average follow-up was 4.2 years (range 1–10 years). Table 3 presents a detailed description of the characteristics of the longitudinal studies. Out of the 54 studies, 53 were candidate gene association studies and the remaining article was a genome-wide association study.


genotypes.

**2.**Cross-sectional studies on genetic associations with muscle phenotypes.

**Table** 









maximal voluntary contraction, TUG: timed up and go.


**Table 3.** Longitudinal studies on genetic association with muscle phenotypes.

#### *Cells* **2020**, *9*, 12







**Table 3.** *Cont*. KE: knee extensor, HG: handgrip, FFM: fat-free mass, AFFM: appendicular fat-free mass, SMI: skeletal muscle index, RT: resistance training, AE: aerobic exercise, CT: tomography, CSA: cross sectional area, 1RM: 1 repetition maximum, PA: physical activity, TUG: timed up and go, ADL: activity of daily living, SPPB: short physical performance

 battery.

A total of 38,112 subjects participated across the 54 studies. Of these, 24,890 (65.3%) were female and 13,222 (34.7%) were male. Thirty-two studies included Caucasians, 13 assessed Asian subjects and the remaining nine studies included Hispanic and African-American participants. As described in the inclusion criteria, all subjects were older than 50 years of age. Thirteen studies included subjects over 50 years of age, 22 studies recruited subjects over 60 years of age and 19 studies included individuals aged 70 years or older.

#### *3.4. Phenotypes and Genotypes*

Of the included studies, 26 reported skeletal muscle mass outcomes, 39 studies included muscle strength testing, 27 articles analysed physical function and six examined sarcopenia prevalence. A full description of the phenotypic outcomes in each study are presented in Tables 2 and 3.

In total, 88 DNA polymorphisms in or near to 26 different genes were analysed across the 54 studies included in this review. The Alpha-actinin 3 (*ACTN3*), Angiotensin Converting Enzyme (*ACE*), and Vitamin D Receptor (*VDR*) genes were the most frequently researched, present in 14, 13 and nine articles, respectively. For clarity and ease of interpretation in the present review, genes are categorised into three main groups: hormone genes, growth factor and cytokine genes and structural and metabolic genes.

#### *3.5. Synthesis of Results*

#### 3.5.1. Hormone Genes
